Compositions And Methods Of Treatment Of Inflammatory Skin Conditions Using Allantoin

ABSTRACT

Embodiments herein provide formulations and methods for treatment of inflammatory skin diseases using allantoin in an amount from about 0.5% to about 15.0% by weight. Inflammatory skin diseases treated by embodiments herein include, without limitation, cutaneous porphyria, sclerodema, epidermolysis bulosa, psoriasis, decubitus ulcers, pressure ulcers, diabetic ulcers, venous stasis ulcers, sickle cell ulcers, ulcers caused by burns, eczema, urticaria, atopic dermatitis, dermatitis herpetiform, contact dermatitis, arthritis, gout, lupus erythematosus, acne, alopecia, carcinomas, psoriasis, rosacea, miliaria, skin infections, post-operative care of incisions, post-operative skin care following any variety of plastic surgery operations, skin care following radiation treatment, care of dry, cracked or aged skin and skin lines as well as other conditions affecting the skin and having an inflammatory component, symptoms thereof, or a combination thereof. Symptoms treated may include pain, inflammation, redness, itching, scarring, skin thickening, milia, or a combination thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application No.61/300,267 filed Feb. 2, 2010 entitled “Compositions and Methods forTreatment of Inflammatory Skin Conditions Using Allantoin,” which isincorporated herein by reference in its entirety.

GOVERNMENT INTERESTS

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PARTIES TO A JOINT RESEARCH AGREEMENT

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INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

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BACKGROUND

Not applicable

BRIEF SUMMARY OF THE INVENTION

Embodiments of the present invention relate generally to compositionscomprising allantoin that can be used to treat individuals affected withinflammatory skin conditions. The compositions are preferably formulatedas topical formulations.

In one aspect, formulations of allantoin comprising from about 2.5% toabout 15% of allantoin by weight and a pharmaceutically acceptableexcipient are provided. In some embodiments, the amount of allantoin isnot 1.5% by weight or less of the composition. In some embodiments, theamount of allantoin is not 2.0% by weight or less of the composition. Inembodiments, the formulation further comprises an emollient, anemulsifier, a solvent, a pH modifier, a solubilizing agent, anantioxidant, a preservative, a chelating agent, an additive, a viscosityagent or a combination thereof. In some embodiments, the formulationcomprises, allantoin in an amount from about 2.5% to about 15% by weightof the formulation, water, cetyl alcohol, stearyl alcohol, beeswax,sodium lauryl sulfate in an about 30% solution, citric acid, lanolinoil, propylene glycol, cod liver oil, butylated hydroxytoluene,methylparaben, propylparaben or a combination thereof. In an embodiment,the formulation may comprise allantoin in an amount of from about 2.5%to about 15%; water in an amount from about 40% to about 90%; cetylalcohol in an amount from about 0.5% to about 15%; stearyl alcohol in anamount from about 1% to about 3%; beeswax in an amount from about 1.5%to about 3%; sodium lauryl sulfate in a 30% solution in an amount fromabout 1.5% to about 3%; citric acid in an amount from about 0.5% toabout 0.2%; lanolin oil in an amount from about 5% to about 15%;propylene glycol in an amount from about 2% to about 8%; tetrasodiumEDTA in an amount from about 0.05% to about 0.5%; cod liver oil in anamount from about 0.05% to about 5%; butylated hydroxytoluene in anamount from about 0.05% to about 1%; methylparaben in an amount fromabout 0.05% to about 0.5%; propylparaben in an amount from about 0.05%to about 0.5% by weight of the formulation or a combination thereof. Inembodiments, the formulation optionally includes tetrasodium EDTA. Inembodiments, the tetrasodium EDTA may be present in an amount from about0.05% to about 0.5% by weight of the formulation. In embodiments, theformulation optionally includes a fragrance. In some embodiments,allantoin may be present in an amount from about 1.5% to about 15%, fromabout 2.0% to about 15%, from about 2.5% to about 15% or from about 3.0%to about 15% by weight of the formulation. In some embodiments, theamount of allantoin is not 1.5% by weight or less of the composition. Insome embodiments, the amount of allantoin is not 2.0% by weight or lessof the composition.

In another aspect, formulations of allantoin comprising about 3.0% ofallantoin, water, cetyl alcohol, stearyl alcohol, beeswax, sodium laurylsulfate in an about 30% solution, citric acid, lanolin oil, propyleneglycol, tetrasodium EDTA, cod liver oil, butylated hydroxytoluene,methylparaben, and propylparaben are provided. In another aspect,formulations of allantoin comprising about 6.0% of allantoin, water,cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in anabout 30% solution, citric acid, lanolin oil, propylene glycol,tetrasodium EDTA, cod liver oil, butylated hydroxytoluene,methylparaben, and propylparaben are provided. In another aspect,formulations of allantoin comprising about 9.0% of allantoin, water,cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in aabout 30% solution, citric acid, lanolin oil, propylene glycol,tetrasodium EDTA, cod liver oil, butylated hydroxytoluene,methylparaben, and propylparaben are provided.

In another aspect, embodiments describe methods of treatment ofinflammatory skin conditions comprising administrating a compositioncomprising from about 2.5% to about 15% allantoin and a pharmaceuticallyacceptable excipient. In some embodiments, the amount of allantoin isnot 1.5% by weight or less of the composition. In some embodiments, theamount of allantoin is not 2.0% by weight or less of the composition. Inembodiments, the composition further comprises an emollient, anemulsifier, a solvent, a pH modifier, a solubilizing agent, anantioxidant, a preservative, a chelating agent, an additive, a viscosityagent or a combination thereof. In some embodiments, the formulationcomprises allantoin, water, cetyl alcohol, stearyl alcohol, beeswax,sodium lauryl sulfate in an about 30% solution, citric acid, lanolinoil, propylene glycol, cod liver oil, butylated hydroxytoluene,methylparaben, propylparaben or a combination thereof. In someembodiments, the formulation comprises allantoin in an amount from about2.5% to about 15%, water in an amount from about 40% to about 90%; cetylalcohol in an amount from about 0.5% to about 15%; stearyl alcohol in anamount from about 1% to about 3%; beeswax in an amount from about 1.5%to about 3%; sodium lauryl sulfate in a 30% solution in an amount fromabout 1.5% to about 3%; citric acid in an amount from about 0.5% toabout 0.2%; lanolin oil in an amount from about 5% to about 15%;propylene glycol in an amount from about 2% to about 8%; cod liver oilin an amount from about 0.05% to about 5%; butylated hydroxytoluene inan amount from about 0.05% to about 1%; methylparaben in an amount fromabout 0.05% to about 0.5%; propylparaben in an amount from about 0.05%to about 0.5% by weight of the formulation or a combination thereof. Inembodiments, the formulation optionally includes tetrasodium EDTA. Inembodiments, the tetrasodium EDTA may be present in an amount from about0.05% to about 0.5% by weight of the formulation. In embodiments, theformulation optionally includes a fragrance. In some embodiments,allantoin may be present in an amount from about 1.5% to about 15%, fromabout 2.0% to about 15%, from about 2.5% to about 15% or from about 3.0%to about 15% by weight of the formulation.

In another aspect, embodiments describe methods of treatment ofinflammatory skin conditions comprising administering a compositioncomprising about 3.0% allantoin and a pharmaceutical excipient. Inanother aspect, embodiments describe methods of treatment ofinflammatory skin conditions comprising administering a compositioncomprising about 6.0% allantoin and a pharmaceutical excipient. Inanother aspect, embodiments describe methods of treatment ofinflammatory skin conditions comprising administering a compositioncomprising about 9.0% allantoin and a pharmaceutical excipient.

In some aspects, the inflammatory skin condition may be characterized byulceration, inflammation, or blistering of the skin. In someembodiments, the inflammatory skin condition may be characterized by agenetic component, an autoimmune component, a circulatory component orcombinations thereof. In some embodiments, the inflammatory skincondition may be selected from a group consisting of cutaneousporphyria, sclerodema, epidermolysis bulosa, psoriasis, decubitusulcers, pressure ulcers, diabetic ulcers, venous stasis ulcers, sicklecell ulcers, ulcers caused by burns, eczema, urticaria, atopicdermatitis, dermatitis herpetiform, contact dermatitis, arthritis, gout,lupus erythematosus, acne, alopecia, carcinomas, psoriasis, rosacea,miliaria, inflammation due to skin infections, post-operative care ofincisions, post-operative inflammation, inflammation following radiationtreatment, inflammation due to dry, cracked or aged skin, skin lines, acombination thereof and a symptom thereof. In some embodiments, thesymptom may be selected from pain, inflammation, itching, scarring,milia, skin thickening, redness, or a combination thereof.

In another aspect, embodiments describe methods of treatment ofEpidermolysis bullosa comprising the topical administration of an about3.0% allantoin containing composition.

In another aspect, embodiments describe methods of treatment ofEpidermolysis bullosa comprising the topical administration of an about6.0% allantoin containing composition.

In another aspect, embodiments describe methods of treatment ofEpidermolysis bullosa comprising the topical administration of an about9.0% allantoin containing composition.

In another aspect, embodiments describe methods of treatment ofpsoriasis comprising the topical administration of an about 3.0%allantoin containing composition.

In another aspect, embodiments describe methods of treatment ofpsoriasis comprising the topical administration of an about 6.0%allantoin containing composition.

In another aspect, embodiments describe methods of treatment ofpsoriasis comprising the topical administration of an about 9.0%allantoin containing composition.

In another aspect, embodiments describe methods of treatment of diabeticulcers comprising the topical administration of an about 3.0% allantoincontaining composition.

In another aspect, embodiments describe methods of treatment of diabeticulcers comprising the topical administration of an about 6.0% allantoincontaining composition.

In another aspect, embodiments describe methods of treatment of diabeticulcers comprising the topical administration of an about 9.0% allantoincontaining composition.

In another aspect, embodiments describe methods of treatment of atopicdermatitis comprising the topical administration of an about 3.0%allantoin containing composition.

In another aspect, embodiments describe methods of treatment of atopicdermatitis comprising the topical administration of an about 6.0%allantoin containing composition.

In another aspect, embodiments describe methods of treatment of atopicdermatitis comprising the topical administration of an about 9.0%allantoin containing composition.

These and other features provided by the present disclosure are setforth herein.

DESCRIPTION OF DRAWINGS

For a fuller understanding of the nature and advantages of the presentinvention, reference should be had to the following detailed descriptiontaken in connection with the accompanying drawings, in which:

FIG. 1 illustrates exemplary formulations of allantoin according toembodiments disclosed herein.

FIG. 2 illustrates an exemplary embodiment of a method of manufacture ofpharmaceutical compositions disclosed herein.

FIG. 3 includes summary tables detailing percutaneous absorption throughvarious barriers over 48 hours from a single application of differentformulations of allantoin.

FIG. 4 is a summary graph detailing percutaneous absorption throughvarious barriers over 48 hours from a single application of differentformulations of allantoin.

FIG. 5 is a summary graph detailing percutaneous absorption throughdermatomed human cadaver skin over 48 hours from a single application offormulations of 9% allantoin.

FIG. 6 is a graph of the results of membrane release of differentformulations of allantoin through a porous membrane.

FIG. 7 includes tables detailing the results of membrane release ofdifferent formulations of allantoin through a porous membrane.

FIG. 8 is a graph of the results for the percutaneous absorption ofdifferent formulations of allantoin through abraded and unabradedporcine cadaver skin.

FIG. 9 includes tables of the results for percutaneous absorption ofdifferent formulations of allantoin through abraded and unabradedporcine cadaver skin.

FIG. 10 is a graph summarizing the percutaneous absorption of differentformulations of allantoin through full thickness human cadaver skin.

FIG. 11 includes tables detailing results for percutaneous absorption ofdifferent formulations of allantoin through full thickness human cadaverskin.

FIG. 12 is a graph summarizing the percutaneous absorption of differentformulations of allantoin through the isolated dermis layer from humancadaver skin.

FIG. 13 includes tables detailing results for percutaneous absorption ofdifferent formulations of allantoin through the isolated dermis layerfrom human cadaver skin.

FIG. 14 is a graph summarizing the percutaneous absorption of 9%allantoin through the isolated dermis layer from human cadaver skin.

FIG. 15 includes tables detailing results for percutaneous absorption of9% allantoin through the isolated dermis layer from human cadaver skin.

1. DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.It is also to be understood that the terminology used in the descriptionis for the purpose of describing the particular versions or embodimentsonly, and is not intended to limit the scope of the present inventionwhich will be limited only by the appended claims. Unless definedotherwise, all technical and scientific terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the preferred methods, devices, and materialsare now described. All publications mentioned herein are incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “fibroblast” is a reference to one or more fibroblasts and equivalentsthereof known to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. In otheraspects, the term “about” means plus or minus 1% of the numerical valueof the number with which it is being used. Therefore, about 50%, meansin the range of 45%-55% or 49.5%-50.5% as described herein.

As used herein, the term “consists of” or “consisting of” means that theformulation includes only the elements, steps, or ingredientsspecifically recited in the particular claimed embodiment or claim.

As used herein, the term “consisting essentially of” or “consistsessentially of” means that the only active pharmaceutical ingredient inthe formulation or method that treats the specified condition (e.g.Epidermolysis bullosa, psoriasis, atopic dermatitis, diabetic ulcers orthe like) is the specifically recited therapeutic in the particularembodiment or claim.

The term “inhibiting” includes the administration of a compound of thepresent invention to prevent the onset of the symptoms, alleviating thesymptoms, or eliminating the disease, condition or disorder.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

As used herein, “room temperature” means an indoor temperature of fromabout 20° C. to about 25° C. (68 to 77° F.).

Unless otherwise indicated, the term “skin” means that outer integumentor covering of the body, consisting of the dermis and the epidermis andresting upon subcutaneous tissue.

The term “improves” is used to convey that the present invention changeseither the appearance, form, characteristics and/or the physicalattributes of the tissue to which it is being provided, applied oradministered. The change in form may be demonstrated by any of thefollowing alone or in combination: enhanced appearance of the skin;decreased inflammation of the skin, prevention of inflammation orblisters, decreased spread of blisters, decreased ulceration of theskin, decreased redness, reduction of scarring, reduction in lesions,healing of blisters, reduced skin thickening, closure of wounds andlesions, a reduction in symptoms including, but not limited to, pain,inflammation, itching, milia or other symptoms associated withinflammatory disease or the like.

As used herein, the term “sole active ingredient” means that the activeingredient or active compound (identified as such) is the only effectivetherapeutic in the formulation to treat the disease or disorder. In someembodiments, allantoin is the sole active ingredient in formulation forthe treatment of inflammatory skin diseases such as Epidermolysisbullosa, psoriasis, atopic dermatitis, diabetic ulcers, or the like. Asan example, in embodiments where a formulation used for the treatment ofpsoriasis contains allantoin as the sole active ingredient, theformulation does not contain another active ingredient, such as, forexample, coal tar.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In part, embodiments of the present invention are directedto the treatment of various skin conditions or disorders, such asinflammatory skin conditions or disorders.

A “therapeutically effective amount” or “effective amount” of acomposition is a predetermined amount calculated to achieve the desiredeffect, i.e., to enhance appearance of skin, to alleviate inflammationor blisters, or to prevent the skin condition from worsening. Theactivity contemplated by the present methods includes both medicaltherapeutic and/or prophylactic treatment, as appropriate. The specificdose of a compound administered according to this invention to obtaintherapeutic and/or prophylactic effects will, of course, be determinedby the particular circumstances surrounding the case, including, forexample, the compound administered, the route of administration, and thecondition being treated. However, it will be understood that theeffective amount administered will be determined by the physician in thelight of the relevant circumstances including the condition to betreated, the choice of compound to be administered, and the chosen routeof administration, and therefore the above dosage ranges are notintended to limit the scope of the invention in any way. Atherapeutically effective amount of compound of this invention istypically an amount such that when it is administered in aphysiologically tolerable excipient composition, it is sufficient toachieve an effective systemic concentration or local concentration inthe tissue.

The terms “treat,” “treated,” or “treating” as used herein refers toboth therapeutic treatment and prophylactic or preventative measures,wherein the object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder or disease, or to obtain beneficial ordesired clinical results. For the purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects.

For example, in some aspects, the invention is directed to a method oftreating a disease using a pharmaceutical composition comprising acompound, as defined above, and a pharmaceutically acceptable carrier ordiluent, or an effective amount of a pharmaceutical compositioncomprising a compound as defined above.

Compounds. The structure of allantoin is:

Encompassed within this disclosure is all forms of allantoin, or a saltthereof, including, but not limited to, crystals, polymorphs,clathrates, solvates, hydrates, amorphous forms, co-crystals, andanhydrous forms. As used herein, “allantoin” includes salts thereof (asdescribed below), crystals, polymorphs, clathrates, solvates, hydrates,amorphous forms, co-crystals, and anhydrous forms unless otherwisespecified.

Embodiments of the present disclosure also relate to the salts ofallantoin. The acids which are used to prepare the salts of theaforementioned compound are those which form non-toxic salts, i.e.,salts containing pharmacologically acceptable anions, such as thehydrochloride, acetate, trifluoroacetic acid, tosylate, picrate,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, lactate, citrate, acid citrate, tartrate, bitartrate,succinate, maleate, fumarate, gluconate, saccharate, benzoate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate salts.

Inflammatory skin disease, particularly chronic inflammatory skindisease, is still a major source of morbidity. Such inflammatory skindiseases are disfiguring and cause severe physical and psychologicalharm to patients, disrupting their quality of life substantially.Inflammatory skin diseases may be selected from genetic inflammatoryskin diseases, circulatory inflammatory skin diseases and auto-immuneinflammatory skin diseases. Such diseases include cutaneous porphyria,sclerodema, epidermolysis bulosa, psoriasis, decubitus ulcers, pressureulcers, diabetic ulcers, venous stasis ulcers, sickle cell ulcers, andulcers caused by burns, as well as other conditions affecting the skinand having an inflammatory component such as eczema, urticaria, atopicdermatitis, dermatitis herpetiform, contact dermatitis, arthritis, gout,and lupus erythematosus. Other skin conditions having an inflammatorycomponent for which improved treatments are needed include acne,alopecia, carcinomas, psoriasis, rosacea, miliaria, skin infections,post-operative care of incisions, post-operative skin care following anyvariety of plastic surgery operations, skin care following radiationtreatment, care of dry, cracked or aged skin and skin lines. Such skindiseases tend to be chronic and difficult to treat, particularly inpatients with poor circulation or other underlying disease states.Symptoms of such diseases may include, without limitation, pain,inflammation, itching, milia, blisters, ulceration, redness, scarring orthe like.

Among the most difficult to treat of these diseases is epidermolysisbullosa. Epidermolysis bullosa (EB) is a rare genetic disorder caused bya mutation in the keratin gene. The disorder is characterized by thepresence of extremely fragile skin, severe inflammation, recurrentblister formation and scarring, resulting from minor mechanical frictionor trauma. Epidermolysis bullosa is difficult to treat by conventionalmeans.

Many allantoin compositions are prepared as emulsions, particularlyoil-in-water emulsions. One emulsifier system used with suchcompositions is a combination of sodium lauryl sulfate and beeswax.Although solutions of sodium lauryl sulfate are alkaline with anapproximate pH of 9.5, the simultaneous use of beeswax with its organicacids produces a complex neutralized system with a pH of about 6.8 toabout 7.5. However, in such a system with a pH range of 6.8 to 7.5,allantoin degrades significantly with time and in accelerated stabilitytests at 40° C. Because preparations designed for application to theskin are typically stored by users at room temperature, and roomtemperatures can fluctuate with climactic conditions, such a degree ofstability is undesirable. Therefore, there is a need for an oil-in-wateremulsified composition containing allantoin in which the stability ofallantoin is increased.

In general, embodiments herein describe a method of treatinginflammatory skin conditions or diseases comprising applying to the skinan allantoin comprising composition in a therapeutically effectiveamount. It was unexpectedly found that stabilized oil-in-water emulsionscontaining allantoin optionally plus other pharmaceutically acceptableingredients as described herein provide a high degree of relief forinflammatory skin conditions characterized by ulceration, inflammation,or blistering of skin. Such skin conditions may include, withoutlimitation, cutaneous porphyria, sclerodema, epidermolysis bullosa,psoriasis, decubitus ulcers, pressure ulcers, diabetic ulcers, venousstasis ulcers, sickle cell ulcers, ulcers caused by burns, eczema,urticaria, atopic dermatitis, dermatitis herpetiform, contactdermatitis, arthritis, gout, lupus erythematosus, acne, alopecia,carcinomas, psoriasis, rosacea, miliaria, skin infections,post-operative care of incisions, post-operative skin care following anyvariety of plastic surgery operations, skin care following radiationtreatment, care of dry, cracked or aged skin and skin lines as well asother conditions affecting the skin and having an inflammatorycomponent. Administration of formulations of allantoin described inembodiments herein may cause a reduction in symptoms of such diseasessuch as, without limitation, pain, scarring, inflammation, redness,milia, itching, skin thickening, blisters, or other symptoms associatedwith inflammatory disease. In some embodiments, inflammatory skindisease may comprise epidermolysis bullosa, psoriasis, atopicdermatitis, and diabetic ulcers. The allantoin-containing compositioncomprises an oil-in-water emulsion as may be described below.

Furthermore, formulations of allantoin in embodiments described hereinmay impart long lasting stability at room temperature (whererefrigeration is not needed) to the formulation. In some embodiments,the formulation may be stable for about 4 to about 10 years, for about 4to about 8 years, for about 4 to about 7 years, for about 4 to about 6years, for about 5 to about 10, for about 5 to about 8 years, for about5 to about 7 years, for about 5 to about 6 years, for about 6 to about10 years, for about 6 to about 8 years, or for about 6 to about 7 years.In some embodiments, stability may include, without limitation, physicalstability, chemical stability, resistance to microbial agents orcombinations thereof. In some embodiments, stability refers to astability of allantoin. In some embodiments, stability refers to aperiod where there is no degradation of allantoin at room temperature.In some embodiments, stability refers to a period where there may beabout 1% or less degradation of allantoin at room temperature. In someembodiments, stability refers to a period where there is no decrease inconcentration. In some embodiments, stability refers to a period wherethere is less than about 1% decrease in concentration. In someembodiments, stability refers to a period of resistance tomicrobiological growth at room temperature. In some embodiments,stability refers to a period where the formulation falls within thenormal bioburden ranges for said formulation at room temperature. Insome embodiments, the formulations of allantoin in embodiments describedherein may impart better absorption of the active pharmaceutical acrossa skin barrier. In some embodiments, the skin barrier comprises intactskin. In some embodiments, the formulations of allantoin in embodimentsdescribed herein may deliver more allantoin across intact skin barrierthan formulations of prior art.

Embodiments of the present disclosure relate to formulations ofallantoin and methods of treatment of inflammatory skin conditions. Insome embodiments, the formulation comprises about 0.5% or more ofallantoin and a pharmaceutically acceptable excipient. In someembodiments, the formulation consists essentially of about 0.5% or moreof allantoin and a pharmaceutically acceptable excipient. In someembodiments, the formulation consists of about 0.5% or more of allantoinand a pharmaceutically acceptable excipient. In some embodiments, theformulation comprises about 1.5% or more of allantoin and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of about 1.5% or more of allantoin anda pharmaceutically acceptable excipient. In some embodiments, theformulation consists of about 1.5% or more of allantoin and apharmaceutically acceptable excipient. In some embodiments, theformulation comprises about 2.0% or more of allantoin and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of about 2.0% or more of allantoin anda pharmaceutically acceptable excipient. In some embodiments, theformulation consists of about 2.0% or more of allantoin and apharmaceutically acceptable excipient. In some embodiments, theformulation comprises about 2.5% or more of allantoin and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of about 2.5% or more of allantoin anda pharmaceutically acceptable excipient. In some embodiments, theformulation consists of about 2.5% or more of allantoin and apharmaceutically acceptable excipient. In some embodiments, theformulation comprises about 3.0% or more of allantoin and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of about 3.0% or more of allantoin anda pharmaceutically acceptable excipient. In some embodiments, theformulation consists of about 3.0% or more of allantoin and apharmaceutically acceptable excipient.

Embodiments describe a composition comprising allantoin in an amountfrom about 0.5% to about 15% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition comprises allantoin inan amount from about 1.5% to about 15% by weight and a pharmaceuticallyacceptable excipient. In some embodiments, the composition comprisesallantoin in an amount from about 2.0% to about 15% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition comprises allantoin in an amount from about 2.5% to about15% by weight and a pharmaceutically acceptable excipient. In someembodiments, the composition comprises allantoin in an amount from about3.0% to about 15% by weight and a pharmaceutically acceptable excipient.In some embodiments, the composition comprises allantoin in an amountfrom about 3.0% to about 10% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition comprises allantoin inan amount from about 3.0% to about 9.0% by weight and a pharmaceuticallyacceptable excipient. In some embodiments, the composition comprisesallantoin in an amount from about 3.0% to about 6.0% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition comprises allantoin in an amount from about 6.0% to about15.0% by weight and a pharmaceutically acceptable excipient. In someembodiments, the composition comprises allantoin in an amount from about6.0% to about 10.0% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition comprises allantoin inan amount from about 6.0% to about 9.0% by weight and a pharmaceuticallyacceptable excipient.

Embodiments describe a composition consisting essentially of allantoinin an amount from about 0.5% to about 15% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists essentially of allantoin in an amount from about1.5% to about 15% by weight and a pharmaceutically acceptable excipient.In some embodiments, the composition consists essentially of allantoinin an amount from about 2.0% to about 15% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists essentially of allantoin in an amount from about2.5% to about 15% by weight and a pharmaceutically acceptable excipient.In some embodiments, the composition consists essentially of allantoinin an amount from about 3.0% to about 15% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists essentially of allantoin in an amount from about3.0% to about 10% by weight and a pharmaceutically acceptable excipient.In some embodiments, the composition consists essentially of allantoinin an amount from about 3.0% to about 9.0% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists essentially of allantoin in an amount from about3.0% to about 6.0% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition consists essentially ofallantoin in an amount from about 6.0% to about 15.0% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists essentially of allantoin in an amount from about6.0% to about 10.0% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition consists essentially ofallantoin in an amount from about 6.0% to about 9.0% by weight and apharmaceutically acceptable excipient.

Embodiments describe a composition consisting of allantoin in an amountfrom about 0.5% to about 15% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition consists of allantoin inan amount from about 1.5% to about 15% by weight and a pharmaceuticallyacceptable excipient. In some embodiments, the composition consists ofallantoin in an amount from about 2.0% to about 15% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists of allantoin in an amount from about 2.5% to about15% by weight and a pharmaceutically acceptable excipient. In someembodiments, the composition consists of allantoin in an amount fromabout 3.0% to about 15% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition consists of allantoin inan amount from about 3.0 to about 10% by weight and a pharmaceuticallyacceptable excipient. In some embodiments, the composition consists ofallantoin in an amount from about 3.0% to about 9.0% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists of allantoin in an amount from about 3.0% to about6.0% by weight and a pharmaceutically acceptable excipient. In someembodiments, the composition consists of allantoin in an amount fromabout 6.0% to about 15.0% by weight and a pharmaceutically acceptableexcipient. In some embodiments, the composition consists of allantoin inan amount from about 6.0% to about 10.0% by weight and apharmaceutically acceptable excipient. In some embodiments, thecomposition consists of allantoin in an amount from about 6.0% to about9.0% by weight and a pharmaceutically acceptable excipient.

In other embodiments, the formulation comprises more than about 1.5% byweight of allantoin, but not 1.5% or less of allantoin, and apharmaceutically acceptable excipient. In some embodiments, theformulation comprises about 2.0% by weight or more of allantoin, but not1.5% or less of allantoin, and a pharmaceutically acceptable excipient.In some embodiments, the formulation comprises about 2.5% by weight ormore of allantoin, but not 1.5% or less of allantoin, and apharmaceutically acceptable excipient. In some embodiments, theformulation comprises about 2.5% by weight or more of allantoin, but notless than 2.0% of allantoin, and a pharmaceutically acceptableexcipient. In some embodiments, the formulation comprises about 3.0% byweight or more of allantoin, but not less than 2.5% of allantoin, and apharmaceutically acceptable excipient. In some embodiments, theformulation comprises about 3.0% by weight or more of allantoin, but notless than 2.0 of allantoin, and a pharmaceutically acceptable excipient.In other embodiments, the formulation comprises about 3.0% by weight ormore of allantoin, but not 1.5% or less of allantoin and apharmaceutically acceptable excipient. In other embodiments, theformulation consists essentially of more than about 1.5% by weight ofallantoin, but not 1.5% or less of allantoin, and a pharmaceuticallyacceptable excipient. In some embodiments, the formulation consistsessentially of about 2.0% by weight or more of allantoin, but not 1.5%or less of allantoin, and a pharmaceutically acceptable excipient. Insome embodiments, the formulation consists essentially of about 2.5% byweight or more of allantoin, but not 1.5% or less of allantoin, and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of about 2.5% by weight or more ofallantoin, but not less than 2.0% of allantoin, and a pharmaceuticallyacceptable excipient. In other embodiments, the formulation consistsessentially of about 3.0%, by weight or more of allantoin, but not lessthan 2.5% of allantoin, and a pharmaceutically acceptable excipient. Insome embodiments, the formulation consists essentially of about 3.0% byweight or more of allantoin, but not less than 2.0% of allantoin and apharmaceutically acceptable excipient. In other embodiments, theformulation consists essentially of about 3.0% by weight or more ofallantoin but not 1.5% or less of allantoin and a pharmaceuticallyacceptable excipient. In other embodiments, the formulation consists ofmore than about 1.5% by weight of allantoin, but not 1.5% or less ofallantoin, and a pharmaceutically acceptable excipient. In someembodiments, the formulation consists of about 2.0% by weight or more ofallantoin, but not 1.5% or less of allantoin, and a pharmaceuticallyacceptable excipient. In some embodiments, the formulation consists ofabout 2.5% by weight or more of allantoin, but not 1.5% or less ofallantoin, and a pharmaceutically acceptable excipient. In someembodiments, the formulation consists of about 2.5% by weight or more ofallantoin, but not less than 2.0% of allantoin, and a pharmaceuticallyacceptable excipient. In some embodiments, the formulation consists ofabout 3.0% by weight or more of allantoin but not less than 2.5% ofallantoin, and a pharmaceutically acceptable excipient. In someembodiments, the formulation consists of about 3.0% by weight or more ofallantoin, but not less than 2.0% of allantoin, and a pharmaceuticallyacceptable excipient. In other embodiments, the formulation consists ofabout 3.0% by weight or more of allantoin, but not 1.5% or less ofallantoin, and a pharmaceutically acceptable excipient.

Embodiments herein describe formulations of allantoin comprising anoil-in-water emulsion comprising allantoin, an emollient, an emulsifierand a solvent. In some embodiments, the formulation further comprises apH modifier, a solubilizing agent, an antioxidant, a preservative, achelating agent, an additive, a viscosity agent or a combinationthereof. In some embodiments, the formulation comprises allantoin, anemollient, an emulsifier, a pH modifier, a solubilizing agent, anantioxidant, a preservative and a solvent. In some embodiments, theformulation consists essentially of allantoin, an emollient, anemulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative and a solvent. In some embodiments, the formulationconsists of allantoin, an emollient, an emulsifier, a pH modifier, asolubilizing agent, an antioxidant, a preservative and a solvent.

The formulations of various embodiments may include any number ofadditional components such as, for example, preservatives, emulsionstabilizers, pH adjusters, chelating agents, viscosity modifiers,anti-oxidants, surfactants, emollients, opacifying agents, skinconditioners, buffers, fragrances, and combinations thereof. In someembodiments, such additional components may provide a dual purpose. Forexample, certain surfactants may also act as emulsifiers, certainemollients may also act as viscosity modifiers, and certain bufferingagents may also act as chelating agents.

In particular, embodiments of the present disclosure relate toformulations of allantoin comprising an oil-in-water emulsion comprisingallantoin; a solvent; an emollient such as, without limitation, lanolinoil, cod liver oil or an alcohol used as a thickening agent; anemulsifier such as, without limitation, sodium laurate sulfate or awhite wax; an antioxidant such as, without limitation, butylatedhydroxytoluene; a preservative such as, without limitation,methylparaben or propylparaben; a pH modifier such as, withoutlimitation, citric acid or lactic acid; and a solubilizing agent suchas, without limitation, glycerin or propylene glycol. In someembodiments, the formulation may further comprise a fragrance, an herbalextract, a viscosity agent such as, without limitation, cetyl alcohol orstearyl alcohol, a chelating agent such as, without limitation,tetrasodium EDTA, or a combination thereof. In some embodiments, theformulation of allantoin comprises any formulation disclosed in FIG. 1.In some embodiments, the formulation of allantoin consists essentiallyof any formulation disclosed in FIG. 1. In some embodiments, theformulation of allantoin consists of any formulation disclosed inFIG. 1. In some embodiments, the formulation of allantoin comprises aformulation selected from the group consisting of 1-206A, 1-192A, 1-196Aand 1-204A as shown in FIG. 1. In some embodiments, the formulation ofallantoin consists essentially of a formulation selected from the groupconsisting of 1-206A, 1-192A, 1-196A and 1-204A as shown in FIG. 1. Insome embodiments, the formulation of allantoin consists of a formulationselected from the group consisting of 1-206A, 1-192A, 1-196A and 1-204Aas shown in FIG. 1. In an embodiment, a formulation of allantoincomprises an oil-in-water emulsion comprising allantoin, water, cetylalcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a 30%solution, citric acid, lanolin oil, propylene glycol, tetrasodium EDTA,cod liver oil, butylated hydroxytoluene, methylparaben, andpropylparaben.

In some embodiments, the formulation may include an emulsifying agent,or emulsifier. In embodiments, the emulsifier may be, for example,sodium lauryl sulfate, white waxes such as beeswax or paraffin wax,sesquioleates such as sorbitan sesquioleate orpolyglyceryl-2-sesquioleate, ethoxylated esters of derivatives ofnatural oils such as the polyethoxylated ester of hydrogenated castoroil, silicone emulsifiers such as silicone polyols, anionic emulsifiers,fatty acid soaps such as potassium stearate and fatty acid sulphateslike sodium cetostearyl sulphate, ethoxylated fatty alcohols, sorbitanesters, ethoxylated sorbitan esters, ethoxylated fatty acid esters suchas ethoxylated stearates, ethoxylated mono, di-, and triglycerides,non-ionic self-emulsifying waxes, ethoxylated fatty acids, methylglucoseesters such as polyglycerol-3 methyl glucose distearate, andcombinations thereof. Various emulsions suitable for embodimentsdescribed herein and methods for preparing such emulsions are well knownin the art and are described in, for example, Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., USA, which is herebyincorporated by reference in its entirety. In some embodiments, theformulation may include an emulsifier in an amount from about 1% toabout 15%, and in other embodiments, the formulation may include fromabout 1% to about 10%, or from about 1% to about 5% emulsifier. If morethan one emulsifier is used, the formulation may include from about 1%to about 5% or from about 1.5% to about 3% by weight of the formulationof each emulsifier.

In some embodiments, the formulations described herein may include oneor more surfactants. Such embodiments are not limited by type ofsurfactant used; for example, in some embodiments, the one or moresurfactants may be anionic surfactants such as alkyl sulfates,alkylether sulfates, alkylsulfonates, alkylaryl sulfonates, alkylsuccinates, alkyl sulfosuccinates, N-alkoylsarcosinates, acyl taurates,acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ethercarboxylates, α-olefinsulfonates, and the alkali metal and alkalineearth metal salts and ammonium and triethanolamine salts thereof. Suchalkyl ether sulfates, alkyl ether phosphates and alkyl ethercarboxylates can have between 1 and 10 ethylene oxide or propylene oxideunits, and in some embodiments, 1 to 3 ethylene oxide units, permolecule. More specific examples include, but are not limited to, sodiumlauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate,ammonium lauryl ether sulfate, sodium lauryl sarcosinate, sodium oleylsuccinate, ammonium lauryl sulfosuccinate, sodium dodecylbenzenesulfonate, triethanolamine dodecylbenzenesulfonate. In otherembodiments, the one or more surfactants may be amphoteric surfactantssuch as, for example, alkylbetaines, alkylamidopropylbetaines,alkylsulfobetaines, alkylglycinates, alkylcarboxyglycinates,alkylamphoacetates or α-propionates, alkylamphodiacetates orα-dipropionates, and more specifically, cocodimethylsulfopropylbetaine,lauryl betaine, cocamidopropylbetaine or sodium cocamphopropionate.

In certain embodiments, the one or more surfactants may be non-ionicsurfactants such as, for example, the reaction products of aliphaticalcohols or alkylphenols having 6 to 20 carbon atoms in a linear orbranched alkyl chain with ethylene oxide and/or propylene oxide wherethe alkylene oxide may be from about 6 moles to about 60 moles per moleof alcohol. In particular embodiments, non-ionic surfactants may includealkylamine oxides, mono- and dialkylalkanolamides, fatty acid esters ofpolyethylenenglycols, ethoxylated fatty acids amides, saturated fattyacid alcohols reacted with ethylene oxide, alkyl polyglycosides, andsorbitan ether esters, and in some embodiments, the non-ionic surfactantmay be ceteareth-2, ceteareth-3, ceteareth-4, ceteareth-5, ceteareth-6,ceteareth-7, ceteareth-8, ceteareth-9, ceteareth-10, ceteareth-11,ceteareth-12, ceteareth-13, ceteareth-14, ceteareth-15, ceteareth-16,ceteareth-17, ceteareth-18, ceteareth-20, ceteareth-22, ceteareth-23,ceteareth-24, ceteareth-25, ceteareth-27, ceteareth-28, ceteareth-29,ceteareth-30, ceteareth-33, ceteareth-34, ceteareth-40, ceteareth-50,ceteareth-55, ceteareth-60, ceteareth-80, ceteareth-100, and the like orcombinations thereof, or one or more ceteareth in combination with afatty acid alcohol such as stearyl alcohol, oleyl alcohol, linoleylalcohol, arachidyl alcohol, cetyl alcohol, and the like. The surfactantof various embodiments may make up from about 0.1% to about 20% byweight of the formulation and in some embodiments, from about 0.5% toabout 20% by weight of the formulation. In embodiments in which morethan one surfactant is provided in the formulation, each surfactant maybe from about 0.5% to about 10% by weight of the formulation, and insome embodiments, each surfactant of the formulation may be from about0.5% to about 6% by weight of the formulation.

In some embodiments, the formulation may comprise emollients in anamount from about 8% to about 30% by weight of the formulation. Informulations that include more than one emollient, each emollient may beprovided at about 0.05% to about 15% by weight of any one emollient.Emollients are well known in the art and are listed, for example, theInternational Cosmetic Ingredient Dictionary, Eighth Edition, 2000,which is hereby incorporated by reference in its entirety. In certainembodiments, the emollient may be fatty esters, fatty alcohols, orcombinations thereof including, but not limited to, diisopropyl adipate,oleyl alcohol, lanolin, isopropyl myristate, isopropyl palmitate,caprylic/capric triglycerides, cetyl lactate, cetyl palmitate,hydrogenated castor oil, glyceryl esters, hydroxycetyl isostearate,hydroxy cetyl phosphate, isopropyl isostearate, isostearyl isostearate,diisopropyl sebacate, polyoxypropylene (5) poloxyethylene (20) cetylether (PPG-5-Ceteth-20), 2-ethylhexyl isononoate, 2-ethylhexyl stearate,C₁₂ to C₁₆ fatty alcohol, C₁₂ to C₁₆ fatty alcohol lactate, isopropyllanolate, 2-ethyl-hexyl salicylate, and combinations thereof. In someembodiments, the one or more emollients may be a combination of fattyalcohols. In certain embodiments, the one or more emollients may be1-hexadecanol, acetylated lanolin, behenocyl dimethicone, C₁₂₋₁₅ alkylbenzoate, cetearyl octanoate, cocoglycerides, dicaprylate/dicapratedimethicone copolyol, dimethiconol, dioctyl adipate, glyceryl stearate,isocetyl alcohol, isohexadecane, isopentylcyclohexanone, isopropylpalmitate, lauryllactate, mineral oil, methoxy peg-22/dodecyl glycolcopolymer, myristyl lactate, ocryldodecyl neopentanoate, octyl cocoate,octyl palmitate, octyl stearate, octyldodecyl neopentanoate,polyglyceryl-4 isosterate, polyoxyl 40 stearate, polyoxymethylene urea,potassium sorbate, propylene glycol, propylene glycol isoceth-3 acetate,and propylene glycol myristyl ether acetate. In some embodiments, theemollient may be a high molecular weight saturated and unsaturated fattyalcohol such as, but not limited to, carbitol, lauryl alcohol, myristylalcohol, cetyl alcohol, isocetyl alcohol, stearyl alcohol, isostearylalcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol,behenyl alcohol, erucyl alcohol, 2-octyldodecanyl alcohol, cetearylalcohol, lanolin alcohol, or the like. In particular embodiments, theemollient may be selected from cetyl alcohol, stearyl alcohol, lanolinoil, cod liver oil, or a combination thereof. In some embodiments, theformulation may comprise an emollient such as, without limitations,cetyl alcohol in an amount from about 2% to about 6%, stearyl alcohol inan amount from about 1% to about 3%, lanolin in an amount from about 5%to about 15%, cod liver oil in an amount from about 0.05% to about 5% orcombinations thereof.

In some embodiments, the formulation may include one or more viscositymodifiers. In some embodiments, the formulation may comprise from about1% to about 10% or from about 1% to about 6% of each viscosity modifier.The viscosity modifier of such embodiments may generally include a highmolecular weight compound such as, for example, carboxyvinyl polymer,carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxyethyl cellulose,methyl cellulose, natural gum such as gelatin and tragacanth gum, andvarious alcohols such as polyvinyl alcohol. In other embodiments, theviscosity modifier may include ethanol or isopropyl alcohol. In someembodiments, the viscosity modifier may be a high molecular weightsaturated and unsaturated fatty alcohol such as, but not limited to,carbitol, lauryl alcohol, myristyl alcohol, cetyl alcohol, isocetylalcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol,oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol,2-octyldodecanyl alcohol, cetearyl alcohol, lanolin alcohol, and thelike, and in certain embodiments, the viscosity modifier may be cetylalcohol, stearyl alcohol or a combination thereof. In some embodiments,the formulation may comprise a viscosity modifier such as, withoutlimitations, cetyl alcohol in an amount from about 2% to about 6%,stearyl alcohol in an amount from about 1% to about 3%, or combinationsthereof.

Formulations of embodiments herein may further include a preservative.For example, preservatives useful in embodiments may include, but arenot limited to, pentylene glycol, ethylene diamine tetra acetate (EDTA)and its salts, chlorhexidine and its diacetate, dihydrochloride,digluconate derivatives, 1,1,1-trichloro-2-methyl-2-propanol,parachlorometaxylenol, polyhexamethylenebiguanide hydrochloride,dehydroacetic acid, diazolidinyl urea, 2,4-dichlorobenzyl alcohol,4,4-dimethyl-1,3-oxazolidine, formaldehyde, glutaraldehyde,dimethylidantoin, imidazolidinyl urea,5-chloro-2-methyl-4-isothiazolin-3-one, ortho-phenylphenol, benzylalcohol, benzoic acid and its salts, 4-hydroxybenzoic acid and itsmethyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-esters(parabens), methylparaben, propylparaben, isopropylparabens,isobutylparabens, butylparabens, ethylparaben, trichlosan,2-phenoxyethanol, phenyl mercuric acetate, quatemium-15,methylsalicylate, salicylic acid and its salts, sorbic acid and itssalts, iodopropanyl butylcarbamate, calcium sorbate, zinc pyrithione,5-bromo-Snitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, sulfites,bisulfites, and benzalkonium chloride, phenoxyethanol, 2-phenoxyethanol,chloroxylenol, diazolidinyl urea, and combinations thereof. In certainembodiments, the formulation may include a combination of methylparabenand propylparaben. Preservatives may be provided in any concentrationknown in the art. For example in some embodiments, the formulation mayinclude preservatives in an amount from about 0.01% to about 3% byweight; and, in embodiments, the formulation may include from about0.05% to about 1% or from about 0.05% to about 0.5% by weight of any onepreservative.

The formulations of various embodiments may further include a chelatingagent or combination of chelating agents. Examples of the chelatingagents useful in various embodiments include, but are not limited to,alanine, sodium polyphosphate, sodium methaphosphate, citric acid,phosphoric acid, tartaric acid, ethylenediamine tetra acetic acid(Edetate, EDTA) and derivatives and salts thereof, dihydroxyethylglycine, and combinations thereof. In particular embodiments, thechelating agent may be tetrasodium EDTA. The chelating agents may beprovided in any effective amount. For example, in some embodiments, theformulation may include from about 0.01% to about 2% by weight chelatingagent, and in other embodiments, the formulation may include from about0.05% to about 0.5% or from about 0.05% to about 0.35% by weightchelating agent.

The formulations of certain embodiments may include one or moreantioxidants. Numerous antioxidants are known in the art, and any suchantioxidant may be used to prepare the formulations described herein.Examples of suitable antioxidants include, but are not limited to, aminoacids such as glycine, histidine, tyrosine, trytophan and derivativesthereof, imidazoles such as urocanic acid and derivatives thereof,peptides, such as D,L-camosine, D-camosine, L-camosine and derivativesthereof such as anserine, carotinoids, carotenes such as α-carotene,β-carotene, lycopene, and derivatives thereof, chlorogenic acid andderivatives thereof, lipoic acid and derivatives thereof such asdihydrlipoic acid, aurothioglycose, propylthiouracil and other thiolssuch as thioredoxin, glutathione, cysteine, cystine, cystamine andglycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl,palmitoyl, oleyl, α-linoleyl, cholesteryl and glyceryl esters and saltsthereof, dilauryl thiodipropionate, distearyl thiodipropionate,thiodipropionic acid and derivatives thereof such as esters, ethers,peptides, lipids, nucleotides, nucleosides, and salts, sulfoximinecompounds such as buthionine sulfoximines, homocysteine sulfoximine,buthionine sulfones, penta-, hexa-, hepta-thionine sulfoximine,unsaturated fatty acids and derivatives thereof such as α-linolenicacid, linoleic acid, oleic acid, folic acid and derivatives thereof,ubiquinone and ubiquinol and derivatives thereof, vitamin C andderivatives there of such as ascorbyl palmitate, magnesium ascorbylphosphate, ascorbyl acetate, tocopherals and derivatives such as vitaminE acetate, vitamin A and derivatives such as vitamin A palmitate,vitamin B and derivatives thereof, coniferyl benzoate of benzoin resin,rutinic acid and derivatives thereof, α-glycosylrutin, ferulic acid,furfurylidene glucitol, carnosine, butyl hydroxytoluene,trihydroxy-butyrophenone, uric acid and derivatives thereof, mannose andderivatives thereof, superoxide dismutase, zinc and derivatives thereofsuch as ZnO, ZnSO₄, selenium and derivatives thereof such as seleniummethionine, stilbene and derivatives thereof such as stilbene oxide,trans-stilbene oxide and the like. In some embodiments, the antioxidantsmay include vitamin B, nordihydroguaiaretic acid, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,erythorbate acid, sodium erythorbate, ascorbir palmitate, and ascorbirstearate. butyl hydroxyanisole, and gallic esters, and in particularembodiments, the one or more antioxidants may include BHT. Theantioxidant may be provided in any suitable amount. For example in someembodiments, one or more antioxidants may be from about 0.001% to about3% by weight of the formulation, and in other embodiments, the one ormore antioxidants may be from about 0.01% to about 1% by weight of theformulation or from about 0.05% to about 1% by weight of theformulation.

In some embodiments, the formulation may include a solubilizing agent.In embodiments, the solubilizers may be, for example, hydrochloric acid,sodium hydroxide, glycine, cyclodextrin, liquid paraffin, hydrogenatedcastor oil, ethanol, glycerin, propylene glycol, dilute hydrochloricacid, hydrogenated oils, purified water, physiological saline, water forinjection, Macrogol 4000, Polysorbate 80, or a combination thereof. Inparticular embodiments, the solubilizing agent may be propylene glycol,glycerin or a combination thereof. In embodiments, the solubilizingagent comprises from about 1% to about 20%, from about 1% to about 10%or from about 2% to about 8% by weight of the formulation.

In certain embodiments, the formulation may include one or moreopacifying agents. In some embodiments, components such as, for example,emollients, surfactants, and/or emulsifiers may provide sufficientopaqueness. In other embodiments, an additional opacifying agent may beprovided to the formulation. Opacifying agents are well known in the artand include, but are not limited to, higher fatty alcohols such ascetyl, stearyl, cetostearyl alcohol, arachidyl and behenyl alcohols,solid esters such as cetyl palmitate, glyceryllaurate, stearamideMEA-stearate, high molecular weight fatty amides and alkanolamides andvarious fatty acid derivatives such as propylene glycol and polyethyleneglycol esters. In other embodiments, opacifying agents may includeinorganic materials such as, for example, magnesium aluminum silicate,zinc oxide, titanium dioxide and other sun-blocking agents. Inembodiments in which an opacifying agent is used, the opacifying agentmay be provided in any amount necessary to provide the desiredopaqueness. In such embodiments, the opacifying agent may generally befrom about 0.01% to about 20% by weight of the formulation, and in someembodiments, the opacifying agent may be from about 0.01% to about 10%or about 0.02% to about 5% by weight of the formulation.

In some embodiments, the formulation may include one or more skinconditioners. Common skin conditioners include, for example, mineraloil, petrolatum, aliphatic alcohols, lanolin and its derivatives, fattyacids, glycol fatty acids, sugars, glycerin, propylene glycol,sorbitols, and polyethylene glycols, vitamins and herbal derivatives.Additional skin conditioners can be found in CTFA Cosmetic IngredientHandbook, 1st Ed., 1988, which is hereby incorporated herein byreference in its entirety. In some embodiments, the one or more skinconditioners may include, but are not limited to, humectants, such asfructose, glucose, glycerin, propylene glycol, glycereth-26, mannitoland urea, pyrrolidone carboxylic acid, hydrolyzed lecithin,coco-betaine, cysteine hydrochloride, glutamine, polyoxypropylene (15)polyoxyethylene (PPG-15), sodium gluconate, potassium aspartate, oleylbetaine, thiamine hydrochloride, sodium laureth sulfate, sodiumhyaluronate, hydrolyzed proteins, hydrolyzed keratin, amino acids, amineoxides, water-soluble derivatives of vitamins A, E and D,amino-functional silicones, ethoxylated glycerin, α-hydroxy acids andsalts thereof, water-soluble fatty oil derivatives, such as PEG-24hydrogenated lanolin, almond oil, grape seed oil and castor oil;numerous other water-soluble skin conditioners listed, and combinationsthereof. In certain embodiments, the skin conditioners may includelanolin or lanolin derivatives, caprylic capric/triglyceride,diisopropyl adipate, and combinations thereof. Skin conditioners may beprovided to various embodiments in any amount known in the art, and theamount of skin conditioner provided may vary depending upon the type ofskin condition or combination of skin conditioners used. In general, theformulations of embodiments may include a conditioner in an amount fromabout 1% to about 30% by weight of the formulation or from about 1% toabout 25% by weight of the formulation.

The pH of various embodiments may be of neutral to mildly acidic pH toallow for comfortable application to a subject's skin, particularly inlight of the disease state or condition suffered by the subject. Forexample, in various embodiments, the pH of the formulations may be fromabout 2.5 to about 7.0, from about 4.0 to about 7.0, or from about 4.0to about 5.5 at room temperature. In other embodiments, the pH of suchformulations may be about 4.0 to about 5.0 at room temperature. Anycomponents or combination of components known and useful in the art maybe used to achieve an appropriate pH such as, for example, pH regulatorsincluding, but not limited to, lactic acid, citric acid, sodium citrate,glycolic acid, succinic acid, phosphoric acid, monosodium phosphate,disodium phosphate, oxalic acid, dl-malic acid, calcium carbonate,sodium hydroxide and sodium carbonate, sodium hydrogen carbonate, andammonium hydrogen carbonate. In particular embodiments, the formulationmay include, for example, citric acid or lactic acid as a pH modifier.In embodiments, the pH modifier may comprise from about 0.01% to about1%, from about 0.05% to about 0.5%, from about 0.06% to about 0.15%,from about 0.06% to about 0.11%, or from about 0.06% to about 0.1% byweight of the formulation.

In embodiments, the formulation may further comprise a solvent. In someembodiments, the solvent may include one or more ingredients therein,with water being preferred in certain embodiments. Generally, thequantity of water used as a solvent may depend on the various otheringredients used. The solvent may be present in certain embodiments in arange of from about 10% to about 95% by weight, with certain embodimentsincluding from about 40% to about 90%, from about 42% to about 87%, fromabout 42% to about 80%, from about 42% to about 75%, from about 42% toabout 70%, or from about 42% to about 68% by weight of the formulation.The exact quantity of solvent may be dependent on the form of theproduct. For example, a product in lotion form may in certain preferredembodiments include more water than a product in spray form and aproduct in cream or butter form may include less water than a product inspray form. Deionized water is generally preferred. Other suitablesolvent materials may also be used.

In embodiments, the formulation of embodiments herein may be physicallyand chemically stable. In some embodiments, the formulation ofembodiments herein may be resistant to microbial agents for up to 4years, up to 6 years, up to 8 years, up to 10 years, up to 12 years orup to 20 years. In some embodiments, the formulation of embodimentsherein may be resistant to microbial agents for from about 4 to about 20years, from about 4 to about 12 years, from about 4 to about 10 years,from about 4 to about 8 years, from about 4 to about 6 years, from about6 to about 20 years, from about 6 to about 12 years, from about 6 toabout 10 years, from about 6 to about 8 years, from about 8 to about 20years, from about 8 to about 12 years, or from about 8 to about 10years.

One embodiment relates to formulations of allantoin comprising anoil-in-water emulsion comprising about 3.0% of allantoin, water, cetylalcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a 30%solution, citric acid, lanolin oil, propylene glycol, tetrasodium EDTA,cod liver oil, butylated hydroxytoluene, methylparaben, andpropylparaben. In further embodiments, the formulation consistsessentially of about 3.0% of allantoin, water, cetyl alcohol, stearylalcohol, beeswax, sodium lauryl sulfate in a 30% solution, citric acid,lanolin oil, propylene glycol, tetrasodium EDTA, cod liver oil,butylated hydroxytoluene, methylparaben, and propylparaben. In certainembodiments, the formulation consists of about 3.0% of allantoin, water,cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a 30%solution, citric acid, lanolin oil, propylene glycol, tetrasodium EDTA,cod liver oil, butylated hydroxytoluene, methylparaben, andpropylparaben. In certain embodiments, the formulation further includesa fragrance. In some embodiments, the fragrance comprises from about0.01% to about 5%, from about 0.01% to about 3%, from about 0.01% toabout 2%, from about 0.01% to about 1% from about 0.01% to about 0.5%,from about 0.05% to about 3%, from about 0.05% to about 2%, from about0.05% to about 1% from about 0.05% to about 0.5% by weight of theformulation. In certain embodiments, the formulation does not contain afragrance. In embodiments, the formulation may further include an herbalextract. In certain embodiments, the formulation does not contain anyherbal extracts.

In another embodiment, formulations of allantoin comprising anoil-in-water emulsion comprising about 6.0% of allantoin, water, cetylalcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a 30%solution, citric acid, lanolin oil, propylene glycol, tetrasodium EDTA,cod liver oil, butylated hydroxytoluene, methylparaben, andpropylparaben are provided. In certain embodiments, the formulation doesnot contain a fragrance. In certain embodiments, the formulation doesnot contain any herbal extracts. In further embodiments, theformulations consist essentially of about 6.0% of allantoin, water,cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a 30%solution, citric acid, lanolin oil, propylene glycol, tetrasodium EDTA,cod liver oil, butylated hydroxytoluene, methylparaben, andpropylparaben. In certain embodiments, the formulations consist of about6.0% of allantoin, water, cetyl alcohol, stearyl alcohol, beeswax,sodium lauryl sulfate in a 30% solution, citric acid, lanolin oil,propylene glycol, tetrasodium EDTA, cod liver oil, butylatedhydroxytoluene, methylparaben, and propylparaben. In certainembodiments, the formulation further includes a fragrance. In certainembodiments, the formulation does not contain a fragrance. Inembodiments, the formulation may further include an herbal extract. Incertain embodiments, the formulation does not contain any herbalextracts.

In another embodiment, formulations of allantoin comprising anoil-in-water emulsion comprising about 9.0% of allantoin, water, cetylalcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a 30%solution, citric acid, lanolin oil, propylene glycol, tetrasodium EDTA,cod liver oil, butylated hydroxytoluene, methylparaben, andpropylparaben are provided. In certain embodiments, the formulation doesnot contain a fragrance. In certain embodiments, the formulation doesnot contain any herbal extracts. In further embodiments, the formulationconsists essentially of about 9.0% of allantoin, water, cetyl alcohol,stearyl alcohol, beeswax, sodium lauryl sulfate in a 30% solution,citric acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod liveroil, butylated hydroxytoluene, methylparaben, and propylparaben. Incertain embodiments, the formulation consists of about 9.0% ofallantoin, water, cetyl alcohol, stearyl alcohol, beeswax, sodium laurylsulfate in a 30% solution, citric acid, lanolin oil, propylene glycol,tetrasodium EDTA, cod liver oil, butylated hydroxytoluene,methylparaben, and propylparaben. In certain embodiments, theformulation further includes a fragrance. In certain embodiments, theformulation does not contain a fragrance. In embodiments, theformulation may further include an herbal extract. In certainembodiments, the formulation does not contain any herbal extracts.

In another embodiment, the formulation comprises about 3.0% allantoin;about 67.01% water; about 3.5% cetyl alcohol; about 1.7% stearylalcohol; about 2.5% beeswax; about 0.09% citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.5% sodium lauryl sulfate in a 30% solution. In furtherembodiments, the formulations consist essentially of about 3.0%allantoin; about 67.01% water; about 3.5% cetyl alcohol; about 1.7%stearyl alcohol; about 2.5% beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.5% sodium lauryl sulfate in a 30% solution. In certainembodiments, the formulations consist of about 3.0% allantoin; about67.01% water; about 3.5% cetyl alcohol; about 1.7% stearyl alcohol;about 2.5% beeswax; about 0.09% citric acid; about 10.6% lanolin oil;about 5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% codliver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.5% sodium lauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 3.0% allantoin;about 67.41% water; about 4.2% cetyl alcohol; about 2% stearyl alcohol;about 1.9% beeswax; about 0.09% citric acid; about 10.6% lanolin oil;about 5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% codliver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and about 1.9% sodium laurylsulfate in a 30% solution. In further embodiments, the formulationconsists essentially of about 3.0% allantoin; about 67.41% water; about4.2% cetyl alcohol; about 2% stearyl alcohol; about 1.9% beeswax; about0.09% citric acid; about 10.6% lanolin oil; about 5.7% propylene glycol;about 0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%propylparaben; and about 1.90% sodium lauryl sulfate in a 30% solution.In certain embodiments, the formulation consists of about 3.0%allantoin; about 67.41% water; about 4.2% cetyl alcohol; about 2%stearyl alcohol; about 1.9% beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; and about 1.9% sodiumlauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 3.0% allantoin;about 67.41% water; about 4.2% cetyl alcohol; about 2% stearyl alcohol;about 1.9% beeswax; about 0.09% citric acid; about 10.6% lanolin oil;about 5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% codliver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and about 1.5% sodium laurylsulfate in a 30% solution. In further embodiments, the formulationsconsist essentially of about 3.0% allantoin; about 67.41% water; about4.2% cetyl alcohol; about 2% stearyl alcohol; about 1.90% beeswax; about0.09% citric acid; about 10.6% lanolin oil; about 5.7% propylene glycol;about 0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%propylparaben; and about 1.5% sodium lauryl sulfate in a 30% solution.In certain embodiments, the formulations consist of about 3.00allantoin; about 67.41% water; about 4.2% cetyl alcohol; about 2%stearyl alcohol; about 1.9% beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; and about 1.5% sodiumlauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 3.0% allantoin;water; cetyl alcohol; stearyl alcohol; beeswax; about 0.09% citric acid;about 10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylatedhydroxytoluene; about 0.3% methylparaben; about 0.25% propylparaben; andabout 2.0% sodium lauryl sulfate in a 30% solution. In furtherembodiments, the formulation consists essentially of about 3.0%allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; about 0.09%citric acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylatedhydroxytoluene; about 0.3% methylparaben; about 0.25% propylparaben; andabout 2.0% sodium lauryl sulfate in a 30% solution. In certainembodiments, the formulation consists of about 3.0% allantoin; water;cetyl alcohol; stearyl alcohol; beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; and about 2.0% sodiumlauryl sulfate in a 300 solution.

In another embodiment, the formulation comprises about 6.0% allantoin;about 63.98% water; about 3.23% cetyl alcohol; about 1.5% stearylalcohol; about 2.75% beeswax; about 0.09% citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.75% sodium lauryl sulfate in a 30% solution. In furtherembodiments, the formulations consist essentially of about 6.0%allantoin; about 63.98% water; about 3.23% cetyl alcohol; about 1.5%stearyl alcohol; about 2.75% beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.75% sodium lauryl sulfate in a 30% solution. In certainembodiments, the formulations consist of about 6.0% allantoin; about63.98% water; about 3.23% cetyl alcohol; about 1.5% stearyl alcohol;about 2.75% beeswax; about 0.09% citric acid; about 10.6% lanolin oil;about 5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% codliver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.75% sodium lauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 6.0% allantoin;about 64.81% water; about 3.5% cetyl alcohol; about 1.5% stearylalcohol; about 2.3% beeswax; about 0.09% citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and about 2.3% sodium laurylsulfate in a 30% solution. In further embodiments, the formulationsconsist essentially of about 6.0% allantoin; about 64.81% water; about3.5% cetyl alcohol; about 1.5% stearyl alcohol; about 2.3% beeswax;about 0.09% citric acid; about 10.6% lanolin oil; about 5.7% propyleneglycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%propylparaben; and about 2.3% sodium lauryl sulfate in a 30% solution.In certain embodiments, the formulations consist of about 6.0%allantoin; about 64.81% water; about 3.5% cetyl alcohol; about 1.5%stearyl alcohol; about 2.3% beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; and about 2.3% sodiumlauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 6.0% allantoin;about 65.11% water; about 3.6% cetyl alcohol; about 1.7% stearylalcohol; about 2.0% beeswax; about 0.09% citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and about 2.0% sodium laurylsulfate in a 30% solution. In further embodiments, the formulationsconsist essentially of about 6.0% allantoin; about 65.11% water; about3.6% cetyl alcohol; about 1.7% stearyl alcohol; about 2.0% beeswax;about 0.09% citric acid; about 10.6% lanolin oil; about 5.7% propyleneglycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%propylparaben; and about 2.0% sodium lauryl sulfate in a 30% solution.In certain embodiments, the formulations consist of about 6.0%allantoin; about 65.11% water; about 3.6% cetyl alcohol; about 1.7%stearyl alcohol; about 2.0% beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; and about 2.0% sodiumlauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 6.0% allantoin;water; cetyl alcohol; stearyl alcohol; beeswax; about 0.09% citric acid;about 10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylatedhydroxytoluene; about 0.3% methylparaben; about 0.25% propylparaben; andabout 1.5% sodium lauryl sulfate in a 30% solution. In furtherembodiments, the formulations consist essentially of about 6.0%allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; about 0.09%citric acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylatedhydroxytoluene; about 0.3% methylparaben; about 0.25% propylparaben; andabout 1.5% sodium lauryl sulfate in a 30% solution. In certainembodiments, the formulations consist of about 6.0% allantoin; water;cetyl alcohol; stearyl alcohol; beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; and about 1.5% sodiumlauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 9.0% allantoin;about 61.78% water; about 2.7% cetyl alcohol; about 1.2% stearylalcohol; about 2.75% beeswax; about 0.12% citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.75% sodium lauryl sulfate in a 30% solution. In furtherembodiments, the formulations consist essentially of about 9.0%allantoin; about 61.78% water; about 2.7% cetyl alcohol; about 1.2%stearyl alcohol; about 2.75% beeswax; about 0.12% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.75% sodium lauryl sulfate in a 30% solution. In certainembodiments, the formulations consist of about 9.0% allantoin; about61.78% water; about 2.7% cetyl alcohol; about 1.2% stearyl alcohol;about 2.75% beeswax; about 0.12% citric acid; about 10.6% lanolin oil;about 5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% codliver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; about 0.2% fragrance; andabout 2.75% sodium lauryl sulfate in a 300 solution.

In another embodiment, the formulation comprises about 9.0% allantoin;about 63.71% water; about 2.5% cetyl alcohol; about 1.2% stearylalcohol; about 2.0% beeswax; about 0.09% citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and about 2.0% sodium laurylsulfate in a 30 solution. In further embodiments, the formulationsconsist essentially of about 9.0% allantoin; about 63.71% water; about2.5% cetyl alcohol; about 1.2% stearyl alcohol; about 2.0% beeswax;about 0.09% citric acid; about 10.6% lanolin oil; about 5.7% propyleneglycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%propylparaben; and about 2.0% sodium lauryl sulfate in a 30% solution.In certain embodiments, the formulations consist of about 9.0%allantoin; about 63.71% water; about 2.5% cetyl alcohol; about 1.2%stearyl alcohol; about 2.0% beeswax; about 0.09% citric acid; about10.6% lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodiumEDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about0.3% methylparaben; about 0.25% propylparaben; and about 2.0% sodiumlauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 9.0% allantoin;water; cetyl alcohol; stearyl alcohol; beeswax; citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and 1.5% sodium lauryl sulfatein a 30% solution. In further embodiments, the formulations consistessentially of about 9.0% allantoin; water; cetyl alcohol; stearylalcohol; beeswax; citric acid; about 10.6% lanolin oil; about 5.7%propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil;about 0.5% butylated hydroxytoluene; about 0.3% methylparaben; about0.25% propylparaben; and 1.5% sodium lauryl sulfate in a 30% solution.In certain embodiments, the formulations consist of about 9.0%allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; citric acid;about 10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylatedhydroxytoluene; about 0.3% methylparaben; about 0.25% propylparaben; and1.5% sodium lauryl sulfate in a 30% solution.

In another embodiment, the formulation comprises about 9.0% allantoin;water; cetyl alcohol; stearyl alcohol; beeswax; citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and sodium lauryl sulfate in a30% solution. In further embodiments, the formulations consistessentially of about 9.0% allantoin; water; cetyl alcohol; stearylalcohol; beeswax; citric acid; about 10.6% lanolin oil; about 5.7%propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil;about 0.5% butylated hydroxytoluene; about 0.3% methylparaben; about0.25% propylparaben; and sodium lauryl sulfate in a 30% solution. Incertain embodiments, the formulations consist of about 9.0% allantoin;water; cetyl alcohol; stearyl alcohol; beeswax; citric acid; about 10.6%lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium EDTA;about 2% cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%methylparaben; about 0.25% propylparaben; and sodium lauryl sulfate in a30% solution.

Embodiments herein are also directed to methods of treating inflammatoryskin conditions comprising administering a composition comprising anoil-in-water emulsion comprising allantoin in an amount from about 0.5%to about 15% by weight and a pharmaceutically acceptable excipient. Insome embodiments, the formulation of allantoin comprises an oil-in-wateremulsion comprising allantoin, an emollient, an emulsifier and asolvent. In some embodiments, the formulation further comprises a pHmodifier, a solubilizing agent, an antioxidant, a preservative, achelating agent, an additive, a viscosity agent or a combinationthereof. In some embodiments, the formulation comprises allantoin, anemollient, an emulsifier, a pH modifier, a solubilizing agent, anantioxidant, a preservative and a solvent. In some embodiments, theformulation consists essentially of allantoin, an emollient, anemulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative and a solvent. In some embodiments, the formulationconsists of allantoin, an emollient, an emulsifier, a pH modifier, asolubilizing agent, an antioxidant, a preservative and a solvent. Insome embodiments, a method of treating inflammatory skin conditions in apatient in need thereof comprises administering a formulation comprisingallantoin, a solvent, an emollient, an emulsifier, an antioxidant, apreservative, a pH modifier and a solubilizing agent, wherein theallantoin is present in an amount of about 0.5% to about 15% by weight.In some embodiments, a method of treating inflammatory skin conditionsin a patient in need thereof comprises administering a formulationconsisting essentially of allantoin, a solvent, an emollient, anemulsifier, an antioxidant, a preservative, a pH modifier and asolubilizing agent, wherein the allantoin is present in an amount ofabout 0.5% to about 15% by weight. In some embodiments, a method oftreating inflammatory skin conditions in a patient in need thereofcomprises administering a formulation consisting of allantoin, asolvent, an emollient, an emulsifier, an antioxidant, a preservative, apH modifier and a solubilizing agent, wherein the allantoin is presentin an amount of about 0.5% to about 15% by weight.

In another embodiment, a method of treating Epidermolysis bullosacomprises administering a formulation of allantoin comprising anoil-in-water emulsion comprising allantoin, an emollient, an emulsifier,a solvent and a pharmaceutically acceptable excipient. In someembodiments, the formulation further comprises a pH modifier, asolubilizing agent, an antioxidant, a preservative, a chelating agent,an additive, a viscosity agent or a combination thereof. In someembodiments, the formulation comprises allantoin, an emollient, anemulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative, a solvent and a pharmaceutically acceptable excipient. Insome embodiments, the formulation consists essentially of allantoin, anemollient, an emulsifier, a pH modifier, a solubilizing agent, anantioxidant, a preservative, a solvent and a pharmaceutically acceptableexcipient. In some embodiments, the formulation consists of allantoin,an emollient, an emulsifier, a pH modifier, a solubilizing agent, anantioxidant, a preservative, a solvent and a pharmaceutically acceptableexcipient. In some embodiments, a method of treating Epidermolysisbullosa in a patient in need thereof comprises administering aformulation comprising allantoin, a solvent, an emollient, anemulsifier, an antioxidant, a preservative, a pH modifier, asolubilizing agent and a pharmaceutically acceptable excipient, whereinthe allantoin is present in an amount of about 0.5% to about 15% byweight. In some embodiments, a method of treating Epidermolysis bullosain a patient in need thereof comprises administering a formulationconsisting essentially of allantoin, a solvent, an emollient, anemulsifier, an antioxidant, a preservative, a pH modifier, asolubilizing agent and a pharmaceutically acceptable excipient, whereinthe allantoin is present in an amount of about 0.5% to about 15% byweight. In some embodiments, a method of treating Epidermolysis bullosain a patient in need thereof comprises administering a formulationconsisting of allantoin, a solvent, an emollient, an emulsifier, anantioxidant, a preservative, a pH modifier, a solubilizing agent and apharmaceutically acceptable excipient, wherein the allantoin is presentin an amount of about 0.5% to about 15% by weight.

In another embodiment, a method of treating psoriasis comprisesadministering a formulation of allantoin comprising an oil-in-wateremulsion comprising allantoin, an emollient, an emulsifier, a solventand a pharmaceutically acceptable excipient. In some embodiments, theformulation further comprises a pH modifier, a solubilizing agent, anantioxidant, a preservative, a chelating agent, an additive, a viscosityagent or a combination thereof. In some embodiments, the formulationcomprises allantoin, an emollient, an emulsifier, a pH modifier, asolubilizing agent, an antioxidant, a preservative, a solvent and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of allantoin, an emollient, anemulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative, a solvent and a pharmaceutically acceptable excipient. Insome embodiments, the formulation consists of allantoin, an emollient,an emulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative, a solvent and a pharmaceutically acceptable excipient. Insome embodiments, a method of treating psoriasis in a patient in needthereof comprises administering a formulation comprising allantoin, asolvent, an emollient, an emulsifier, an antioxidant, a preservative, apH modifier, a solubilizing agent and a pharmaceutically acceptableexcipient, wherein the allantoin is present in an amount of about 0.5%to about 15% by weight. In some embodiments, a method of treatingpsoriasis in a patient in need thereof comprises administering aformulation consisting essentially of allantoin, a solvent, anemollient, an emulsifier, an antioxidant, a preservative, a pH modifier,a solubilizing agent and a pharmaceutically acceptable excipient,wherein the allantoin is present in an amount of about 0.5% to about 15%by weight. In some embodiments, a method of treating psoriasis in apatient in need thereof comprises administering a formulation consistingof allantoin, a solvent, an emollient, an emulsifier, an antioxidant, apreservative, a pH modifier, a solubilizing agent and a pharmaceuticallyacceptable excipient, wherein the allantoin is present in an amount ofabout 0.5% to about 15% by weight. As shown in Example 11, it isbelieved that formulations containing above 1.5% allantoin are betterable to treat psoriasis than formulations of 1.5% or below. Accordingly,embodiments herein include a method of treating psoriasis disclosedherein wherein allantoin is present an amount greater than about 1.5% toabout 15%.

In another embodiment, a method of treating diabetic ulcers comprisesadministering a formulation of allantoin comprising an oil-in-wateremulsion comprising allantoin, an emollient, an emulsifier, a solventand a pharmaceutically acceptable excipient. In some embodiments, theformulation further comprises a pH modifier, a solubilizing agent, anantioxidant, a preservative, a chelating agent, an additive, a viscosityagent or a combination thereof. In some embodiments, the formulationcomprises allantoin, an emollient, an emulsifier, a pH modifier, asolubilizing agent, an antioxidant, a preservative, a solvent and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of allantoin, an emollient, anemulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative, a solvent and a pharmaceutically acceptable excipient. Insome embodiments, the formulation consists of allantoin, an emollient,an emulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative, a solvent and a pharmaceutically acceptable excipient. Insome embodiments, a method of treating diabetic ulcers in a patient inneed thereof comprises administering a formulation comprising allantoin,a solvent, an emollient, an emulsifier, an antioxidant, a preservative,a pH modifier, a solubilizing agent and a pharmaceutically acceptableexcipient, wherein the allantoin is present in an amount of about 0.5%to about 15% by weight. In some embodiments, a method of treatingdiabetic ulcers in a patient in need thereof comprises administering aformulation consisting essentially of allantoin, a solvent, anemollient, an emulsifier, an antioxidant, a preservative, a pH modifier,a solubilizing agent and a pharmaceutically acceptable excipient,wherein the allantoin is present in an amount of about 0.5% to about 15%by weight. In some embodiments, a method of treating diabetic ulcers ina patient in need thereof comprises administering a formulationconsisting of allantoin, a solvent, an emollient, an emulsifier, anantioxidant, a preservative, a pH modifier, a solubilizing agent and apharmaceutically acceptable excipient, wherein the allantoin is presentin an amount of about 0.5% to about 15% by weight.

In another embodiment, a method of treating atopic dermatitis comprisesadministering a formulation of allantoin comprising an oil-in-wateremulsion comprising allantoin, an emollient, an emulsifier, a solventand a pharmaceutically acceptable excipient. In some embodiments, theformulation further comprises a pH modifier, a solubilizing agent, anantioxidant, a preservative, a chelating agent, an additive, a viscosityagent or a combination thereof. In some embodiments, the formulationcomprises allantoin, an emollient, an emulsifier, a pH modifier, asolubilizing agent, an antioxidant, a preservative, a solvent and apharmaceutically acceptable excipient. In some embodiments, theformulation consists essentially of allantoin, an emollient, anemulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative, a solvent and a pharmaceutically acceptable excipient. Insome embodiments, the formulation consists of allantoin, an emollient,an emulsifier, a pH modifier, a solubilizing agent, an antioxidant, apreservative, a solvent and a pharmaceutically acceptable excipient. Insome embodiments, a method of treating atopic dermatitis in a patient inneed thereof comprises administering a formulation comprising allantoin,a solvent, an emollient, an emulsifier, an antioxidant, a preservative,a pH modifier, a solubilizing agent and a pharmaceutically acceptableexcipient, wherein the allantoin is present in an amount of about 0.5%to about 15% by weight. In some embodiments, a method of treating atopicdermatitis in a patient in need thereof comprises administering aformulation consisting essentially of allantoin, a solvent, anemollient, an emulsifier, an antioxidant, a preservative, a pH modifier,a solubilizing agent and a pharmaceutically acceptable excipient,wherein the allantoin is present in an amount of about 0.5% to about 15%by weight. In some embodiments, a method of treating atopic dermatitisin a patient in need thereof comprises administering a formulationconsisting of allantoin, a solvent, an emollient, an emulsifier, anantioxidant, a preservative, a pH modifier, a solubilizing agent and apharmaceutically acceptable excipient, wherein the allantoin is presentin an amount of about 0.5% to about 15% by weight.

Embodiments of the present disclosure also relate to the use offormulations of allantoin in connection with excipients or stabilizers.Stabilizers include carbohydrates, amino acids, fatty acids, andsurfactants and are known to those skilled in the art.

Compositions according to the embodiments described herein can containother, optional ingredients. For example, compositions according to thepresent embodiments can contain glycerin, lactic acid, lipid-solublecomponents such as, but not limited to, caprylic/capric triglycerides;steareth-2; steareth-21; polygrlyceryl-3 beeswax; a branched-carboxylicacid ester of a branched-chain alcohol selected from the groupconsisting of isononyl isononanoate, isodecyl isononanoate, isooctylisononanotate, isooctyl isooctanoate, isononyl isooctanoate, isodecylisooctanoate, isononyl isodecanoate, isooctyl isodecanoate, and isodecylisodecanoate; an acrylates/C₁₀-C₃₀ alkyl acrylates cross-polymer;methylgluceth-20; a glyceryl ester of a long chain fatty acid selectedfrom the group consisting of glyceryl monostearate, glycerylmonopalmitate, and glyceryl monoarachidate; hydrogenated vegetable oil;squalane; C₁₂-C₁₅ alkyl benzoates; di-C₁₂-C₁₅ alkyl fumarate;cholesterol; lanolin alcohol; octyldodecanol, isostearic acid; abranched-chain neopentanoate selected from the group consisting ofoctyldodecyl neopentanoate, heptyldodecyl neopentanoate, nonyldodecylneopentanoate, octylundecyl neopentanoate, heptylundecyl neopentanoate,nonylundecyl neopentanoate, octyltridecyl neopentanoate, heptyltridecylneopentanoate, and nonyltridecyl neopentanoate; an arachidyl ester of ashort-chain carboxylic acid selected from the group consisting ofarachidyl propionate, arachidyl acetate, arachidyl butyrate, andarachidyl isobutyrate; a long-chain fatty acid ester of a medium-chainalcohol selected from the group consisting of octyl palmitate, octylmyristate, octyl stearate, heptyl palmitate, heptylmyristate, heptylstearate, nonyl palmitate, nonyl myristate, and nonyl stearate; jojobaoil; a myristyl ester of a long-chain fatty acid selected from the groupconsisting of myristyl myristate, myristyl laurate, and myristylpalmitate; bisabolol; hydrogenated jojoba oil; jojoba esters;methyl-gluceth-20 sesquistearate; PPG-14 butyl ether; PPG-15 stearylether; PPG-1-isoceteth-3-accetate; laureth-2-benzoate; diisostearyldimmer dilinoleate; a long-chain cis-monounsaturated fatty acid ester ofa medium-chain alcohol; a medium-chain saturated carboxylic acid esterof a long-chain alcohol; hydrogenated soy glycerides; a long-chain fattyacid ester of cetyl alcohol selected from the group consisting of cetylpalmitate, cetyl stearate, and cetyl myristate; palm kernel oil; palmoil; and an arachidyl ester such as arachidyl acetate, arachidylpropionate, arachidyl butyrate, or arachidyl isobutyrate.

In addition, the composition can further comprise other ingredients thatare generally used in the cosmetic art and in the art ofover-the-counter skin preparations. These ingredients include, but arenot limited to: (1) other plant extracts, such as horsetail extract,horse chestnut extract, rose extract, or lavender extract; (2) ashort-chain carboxylic acid ester of tocopherol selected from the groupconsisting of tocopheryl acetate, tocopheryl propionate, tocopherylbutyrate, and tocopheryl isobutyrate; (3) a long-chain fatty acid esterof ascorbic acid selected from the group consisting of ascorbylmyristate, ascorbyl palmitate, and ascorbyl stearate; (4) a long-chainfatty acid ester of retinol or a retinol derivative or analogue whereinthe acyl moiety of the ester is selected from the group consisting ofmyristic acid, palmitic acid, and stearic acid; and (5) a sunscreen,which can be at least one compound selected from the group consisting ofoctyl methoxycinnamate, p-aminobenzoate, glyceryl p-aminobenzoate,p-dimethylaminobenzoic acid, methyl anthranilate, menthyl anthranilate,phenyl anthranilate, benzyl anthranilate, phenylethyl anthranilate,linalyl anthranilate, terpinyl anthranilate, cyclohexenyl anthranilate,amyl salicylate, phenyl salicylate, benzyl salicylate, menthylsalicylate, glyceryl salicylate, dipropyleneglycol salicylate, methylcinnamate, benzyl cinnamate, α-phenyl cinnamonitrile, butylcinnamoylpyruvate, umbelliferone, methylacetoumbelliferone, esculetin,methylesculetin, daphnetin, esculin, daphnin, diphenylbutadiene,stilbene, dibenzalacetone, benzalacetophenone, sodium2-naphthol-3,6-disulfonate, sodium 2-naphthol-6,8-disulfonate,dihydroxynaphthoic acid, salts of dihydroxynaphthoic acid,o-hydroxybiphenyldisulfonates, p-hydroxybiphenyldisulfonates,7-hydroxycoumarin, 7-methylcoumarin, 3-phenyl-coumarin,2-acetyl-3-bromoindazole, phenylbenzoxazole, methylnaphthoxazole,arylbenzothiazoles, quinine bisulfate, quinine sulfate, quininechloride, quinine oleate, quinine tannate, 8-hydroxyquinoline salts,2-phenylquinoline, hydroxyl-substituted benzophenones,methoxy-substituted benzophenones, uric acid, vilouric acid, tannicacid, tannic acid hexaethylether, hydroquinone, oxybenzone,sulisobenzone, dioxybenzone, benzoresorcinol,2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4-dimethoxybenzophenone, octabenzone,butylmethoxydibenzoylmethane, etocrylene, and4-isopropyldibenzoylmethane. Other ingredients can also optionally beincluded, such as colorants, pigments, opacifiers, and the like.

Methods according to the embodiments described herein provide rapidimprovement, are well tolerated by patients, are easy to apply, and canbe used alone or with other methods for treatment of skin conditions.Alternative formulations with reduced sodium lauryl sulfate, reducedbeeswax and no fragrance are better suited to treat diseases such asEpidermolysis bullosa, where the skin is fragile and sensitive toirritants. It was unexpectedly found that these formulations, thoughthey have reduced sodium lauryl sulfate and reduced beeswax, have astable emulsion in room temperatures and are effective in treatinginflammatory skin conditions. In particular, formulations of embodimentsherein have better penetration of intact skin and are able to deliverthe active (i.e. allantoin) across intact skin.

In any of the foregoing embodiments, the composition can further includefragrance. The use of fragrance is well known in the art ofover-the-counter drug formulation, and many suitable fragrances areknown in the art. The stability and function of the composition is notaltered by the presence or absence of fragrance. In many alternatives,it may be desirable to avoid the use of fragrance which may triggerallergic reaction in patients predisposed to such reactions.Accordingly, in certain embodiments, the composition excludes afragrance.

The compositions can further include other ingredients, such asproteins, humectants, other preservatives, essential oils, othervitamins, colorants, hydroxyacids, other plant extracts, sunscreens,sodium hyaluronate, lipids, fatty acids, thickeners, panthenol, and thelike. The use of such components is conventional in the over-the-counterdrug art. Typical sunscreens are octyl methoxycinnamate andbenzophenone-3.

In any of the foregoing embodiments, the term “inflammatory skinconditions” is used interchangeably with “inflammatory skin diseases”and includes cutaneous porphyria, sclerodema, epidermolysis bullosa,psoriasis, decubitus ulcers, pressure ulcers, diabetic ulcers, venousstasis ulcers, sickle cell ulcers, ulcers caused by burns, eczema,urticaria, atopic dermatitis, dermatitis herpetiform, contactdermatitis, arthritis, gout, lupus erythematosus, acne, alopecia,carcinomas, psoriasis, rosacea, miliaria, skin infections,post-operative care of incisions, post-operative skin care following anyvariety of plastic surgery operations, skin care following radiationtreatment, care of dry, cracked or aged skin and skin lines as well asother conditions affecting the skin and having an inflammatorycomponent. The term may also include symptoms associated with suchdiseases such as, without limitation, pain, scarring, inflammation,redness, milia, itching, skin thickening, blisters, or other symptomsassociated with inflammatory disease.

Pharmaceutical Compositions.

Pharmaceutical compositions provided by the present disclosure maycomprise formulations of allantoin and in certain embodiments, inpurified form, together with a suitable amount of one or morepharmaceutically acceptable vehicles, so as to provide a composition forproper administration to a patient with an inflammatory skin disease.Suitable pharmaceutical vehicles also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol, and thelike. The present compositions may also contain wetting agents,emulsifying agents, and/or pH buffering agents. In addition, auxiliary,stabilizing, thickening, lubricating, and/or coloring agents may beused. Other examples of suitable pharmaceutical vehicles are describedin the art (see, for example, “Remington's Pharmaceutical Sciences,”Lippincott Williams & Wilkins, 21st Edition, 2005).

Pharmaceutical compositions disclosed herein may be prepared by standardmixing techniques, such as are conventional in the cosmetic art and inthe art of over-the-counter drug formulation for blending lipid-solublecomponents and water-soluble components. These mixing techniques includeboth manual and mechanical mixing, and include homogenization mixing andsweep mixing. The mixing techniques to be used can be chosen by one ofordinary skill in the art based on variables such as the viscosity ofthe components to be mixed and the volume of those components, as wellas the relative proportion of lipid-soluble and water-solubleingredients. The composition can be mixed in two or more batches, suchas one batch containing lipid-soluble ingredients and another batchcontaining water-soluble ingredients, and the batches can then be mixedat the final state of preparation.

For example, pharmaceutical compositions disclosed herein may bemanufactured by following these steps: (1) mix and heat water, 30%solution of sodium lauryl sulfate, propylene glycol, tetrasodium EDTAand citric acid in one container (“Container 1”); (2) in anothercontainer (“Container 2”), mix and heat lanolin oil, beeswax, stearylalcohol and cetyl alcohol; (3) when both containers reach about 170-180°F., add contents of Container 2 to Container 1; (4) add cod liver oiland butyl hydroxytoluene (BHT); (5) mix for about thirty minutes; (6)add allantoin; (7) mix for about thirty minutes; (8) cool contents toabout 120° F.; (9) add methylparaben and propylparaben; (10) mix forabout ten minutes; (11) remove the mixer and insert the homogenizer;(12) activate the homogenizer for about five minutes; (13) remove thehomogenizer and insert mixer; (14) mix for about thirty minutes whilemaintaining temperature range of about 115-120° F.; (15) continue mixingwhile contents are cooled to about 115° F.; (16) stop mixing whencontents reach about 115° F.; (17) remove mixer and cover drum; (18)store cream overnight at room temperature; and (19) package the creaminto finished product containers.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers, diluents,excipients, or auxiliaries, which facilitate processing of allantoin andone or more pharmaceutically acceptable vehicles into formulations thatcan be used pharmaceutically. Proper formulation is dependent upon theroute of administration chosen.

Pharmaceutical compositions provided by the present disclosure may beadministered for therapeutic or prophylactic treatments. A therapeuticamount is an amount sufficient to remedy a disease state or symptoms, orotherwise prevent, hinder, retard, or reverse the progression of diseaseor any other undesirable symptoms in any way whatsoever. In prophylacticapplications, pharmaceutical compositions or the present disclosure maybe administered to a patient susceptible to or otherwise at risk of aparticular disease or infection. Hence, a prophylactically effectiveamount is an amount sufficient to prevent, hinder or retard a diseasestate or its symptoms.

Specific modes of administration will depend on the indication. Theselection of the specific route of administration and the dose regimenis to be adjusted or titrated by the clinician according to methodsknown to the clinician in order to obtain the optimal clinical response.The amount of compound to be administered is that amount which istherapeutically effective. The dosage to be administered will depend onthe characteristics of the subject being treated, e.g., the particularanimal treated, age, weight, health, types of concurrent treatment, ifany, and frequency of treatments, and can be easily determined by one ofskill in the art (e.g., by the clinician).

Pharmaceutical formulations containing the above-described compound anda suitable carrier can be topical dosage forms which include, but arenot limited to, solutions, powders, fluid emulsions, fluid suspensions,semi-solids, ointments, pastes, creams, gels and jellies, and foamscomprising an effective amount of a polymer or copolymer of the presentembodiment. It is also known in the art that the active ingredients canbe contained in such formulations with pharmaceutically acceptablediluents, fillers, disintegrants, binders, lubricants, surfactants,hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers,humectants, moisturizers, solubilizers, preservatives and the like. Themeans and methods for administration are known in the art and an artisancan refer to various pharmacologic references for guidance. For example,Modem Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); andGoodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6thEdition, MacMillan Publishing Co., New York (1980) can be consulted.

The embodiments illustrating the methods and materials used may befurther understood by reference to the following non-limiting examples.

Example 1

A formulation containing 3.0% allantoin; 67.01% water; 3.5% cetylalcohol; 1.7% stearyl alcohol; 2.5% beeswax; 0.09% citric acid; 10.6%lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liveroil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%propylparaben; 0.2% fragrance; and 2.5% sodium lauryl sulfate in a 30%solution was made. The pH of this formulation is 4.58.

Example 2

A formulation containing 3.0% allantoin; 67.41% water; 4.2% cetylalcohol; 2% stearyl alcohol; 1.9% beeswax; 0.09% citric acid; 10.6%lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liveroil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%propylparaben; and 1.9% sodium lauryl sulfate in a 30% solution wasmade. The pH of this formulation is 4.54. It is desirous to reduceirritants due to the indications of these inflammatory skin conditions;thus we reduced the amounts of beeswax, and sodium lauryl sulfate andremoved the fragrance. It was unexpected that such a reduction of theseingredients created an effective composition because lowering theemulsifier concentration may not result in a system that demonstrateslong-term stability.

Example 3

A formulation containing 3.0% allantoin; water; cetyl alcohol; stearylalcohol; beeswax; 0.09% citric acid; 10.6% lanolin oil; 5.7% propyleneglycol; 0.15% tetrasodium EDTA; 2% cod liver oil; 0.5% butylatedhydroxytoluene; 0.3% methylparaben; 0.25% propylparaben; and 1.5% sodiumlauryl sulfate in a 30% solution was made. It is desirous to reduceirritants due to the indications of these inflammatory skin conditions;thus we reduced the amounts of beeswax, and sodium lauryl sulfate andremoved the fragrance. It was unexpected that such a reduction of theseingredients created an effective composition because lowering theemulsifier concentration may not result in a system that demonstrateslong-term stability at room temperature.

Example 4

A formulation containing 6.0% allantoin; 63.98% water; 3.23% cetylalcohol; 1.5% stearyl alcohol; 2.75% beeswax; 0.09% citric acid; 10.6%lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liveroil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%propylparaben; 0.2% fragrance; and 2.75% sodium lauryl sulfate in a 30%solution was made. The pH of this formulation is 4.62.

Example 5

A formulation containing 6.0% allantoin; 64.81% water; 3.5% cetylalcohol; 1.5% stearyl alcohol; 2.3% beeswax; 0.09% citric acid; 10.6%lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liveroil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%propylparaben; and 2.3% sodium lauryl sulfate in a 30% solution wasmade. The pH of this formulation is 4.51. It is desirous to reduceirritants due to the indications of these inflammatory skin conditions;thus we reduced the amounts of beeswax, and sodium lauryl sulfate andremoved the fragrance. It was unexpected that such a reduction of theseingredients created an effective composition because lowering theemulsifier concentration may not result in a system that demonstrateslong-term stability at room temperature.

Example 6

A formulation containing 6.0% allantoin; 65.11% water; 3.6% cetylalcohol; 1.7% stearyl alcohol; 2.0% beeswax; 0.09% citric acid; 10.6%lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liveroil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%propylparaben; and 2.0% sodium lauryl sulfate in a 30% solution wasmade. It is desirous to reduce irritants due to the indications of theseinflammatory skin conditions; thus we reduced the amounts of beeswax,and sodium lauryl sulfate and removed the fragrance. It was unexpectedthat such a reduction of these ingredients created an effectivecomposition because lowering the emulsifier concentration may not resultin a system that demonstrates long-term stability at room temperature.

Example 7

This formulation contained 9.0% allantoin; 61.78% water; 2.7% cetylalcohol; 1.2% stearyl alcohol; 2.75% beeswax; 0.12% citric acid; 10.6%lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liveroil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%propylparaben; 0.2% fragrance; and 2.75% sodium lauryl sulfate in a 30%solution. The pH of this formulation is 4.07.

Example 8

This formulation contained 9.0% allantoin; water; cetyl alcohol; stearylalcohol; beeswax; citric acid; 10.6% lanolin oil; 5.7% propylene glycol;0.15% tetrasodium EDTA; 2% cod liver oil; 0.5% butylated hydroxytoluene;0.3% methylparaben; 0.25% propylparaben; and sodium lauryl sulfate in a30% solution. It is desirous to reduce irritants due to the indicationsof these inflammatory skin conditions; thus we reduced the amounts ofbeeswax, and sodium lauryl sulfate and removed the fragrance. It wasunexpected that such a reduction of these ingredients created aneffective composition because lowering the emulsifier concentration maynot result in a system that demonstrates long-term stability at roomtemperature.

Example 9

This formulation contained 90% allantoin; 63.71% water; 2.5% cetylalcohol; 1.2% stearyl alcohol; 2.0% beeswax; 0.09% citric acid; 10.6%lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liveroil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%propylparaben; and 2.0% sodium lauryl sulfate in a 30% solution. It isdesirous to reduce irritants due to the indications of theseinflammatory skin conditions; thus we reduced the amounts of beeswax,and sodium lauryl sulfate and removed the fragrance. It was unexpectedthat such a reduction of these ingredients created an effectivecomposition because lowering the emulsifier concentration may not resultin a system that demonstrates long-term stability at room temperature.

Example 10

The formulations A.S. 1-139E, A.S. 1-81B, A.S. 1-135C, A.S. 1-1350, andA.S. 1-81G were tested on a minimum of triplicate sections from threedifferent cadaver skin donors and three different porcine skin donorsfor the percutaneous absorption of allantoin over a 48-hour dose period.The intent of this study was to mimic the absorption of allantoindirectly into the capillary bed, while the dermis only study attemptedto mimic the loss of skin barrier function due to broken skin orblisters. In addition, each formulation was tested in at leasttriplicate membrane chambers. At preselected times after dosing, thedermal receptor solution was removed in its entirety, replaced withfresh receptor solution, and an aliquot saved for subsequent analysis.The samples were analyzed for the allantoin using high performanceliquid chromatography with UV and MS detection (HPLC-UV-MS). The summaryresults are presented in FIG. 3 and FIG. 4. The bottom table of FIG. 3lists a remanufacture of the 9% allantoin cream (A.S. 1-153H) to achievea better viscosity of the final product. That table demonstrates thatthe initial results with A.S. 1-81G were lower than expected andunreliable due to problems in the manufacture of this lot. Theremanufacture of the new A.S. 1-153H 9% lot demonstrated no viscosityissues, and was retested in the full thickness skin model only,demonstrating that the penetration of allantoin with this concentrationwas two times that of the 6% formulation (A.S. 1-135G). It can also beinferred based on this result that the 9% cream results in the top tableof FIG. 3 may be higher than reported with A.S. 1-81G and dose relatedto the other formulation concentrations in all percutaneous models.

Conclusions: Analysis of the mass delivered through the porous membraneover 24 hours (FIGS. 6-7) showed that 9%>6%>3%>1.5%>0.5% (p<0.05). Areaunder the curve presented graphically demonstrated a dose-relatedincrease in allantoin penetration across the membrane. Analysis of themass delivered through full thickness human cadaver skin (FIGS. 10-11)showed that 6% delivered more than 0.5% (p<0.05), and that penetrationacross the skin was related to the concentration of allantoin in theformulation. The accuracy of the formulation's manufacturing impactedthe ability of the formulation to deliver allantoin across the skin, asdemonstrated by a 2× increase in allantoin delivered across the intactskin with the new 9% lot (A.S. -153H) versus the previous 9% lot (A.S.1-81G), which was outside of specifications in terms of physicalappearance and consistency.

Statistical analysis of the mass delivered through dermis only humancadaver skin (FIGS. 12-15) showed that 9%>6%>3%>1.5%>0.5% (p<0.05). Itis well known from studies with dermal formulations that the lack ofefficacy of dermal products is due to lack of penetration of the activeingredient across the stratum corneum, which is an effective barrier,however the formulations described above delivered allantoin across thisstratum corneum in a dose related manner, unexpectedly. When the skin'sbarrier has been damaged or removed (as seen with the isolated dermis inFIGS. 12-15), the penetration of allantoin increases significantly.

Blood and urine collection and analysis for the presence of allantoindemonstrated no increase in basal levels of allantoin in either theblood or urine from EB patients treated with 1.5% allantoin daily for aperiod greater than 1 year. In addition, data derived from various skinpenetration models (dermis and full thickness cadaver skin, abradedporcine skin, and membrane) demonstrated a dose-related increase inallantoin concentrations across various skin models, which was clearlyunexpected due to lack of penetration enhancers in the formulation.Specifically, allantoin levels increased from 1.5 to 3× across thedermis in the 3%, 6%, and 9% formulations; 2.5 to 7× across the fullthickness skin; and 2-4× across the membrane, as compared to a 1.5%formulation. Additionally, it was unexpected that the allantoinformulations result in penetration of allantoin across the skin membranewithout any increase in systemic blood levels.

The results of the penetration studies with the various concentration ofthe active ingredient, allantoin, was clearly unexpected, given therobustness of the protection of the skin from penetration of topicalproducts. This formulation was able to deliver allantoin across all skinmodels in a dose-related manner over a sustained period of time. Theinability of deliver of active ingredients across the intact skin anddermal barriers is the reason why topical products typically only workon superficial skin diseases.

Example 11

In vitro tests confirm the protein dispersing activity of allantoin asmeasured by the concentration of reactive sulphydryl groups releasedfrom the protein of skin samples. Keratolytic activity on psoriaticscales was demonstrated in vitro by incubation with concentrations aslow as 0.2% allantoin solution. (Fisher A 1981; Cajkovac et al 1992).Keratolysis is a process whereby horny cells are dispersed with arelease of non-keratinous material such as free amino acids and acidmucopolysaccharides which contributes to the horny layer associated withpsoriasis (Flesch 1958). Other studies have further demonstrated theability of allantoin to remove or reduce calluses and other forms ofhyperkeratization by dissolving the cement holding the cornified cellstogether, or loosening of the desmosomes as lower concentrations(<1%)(protein bridges) (Mecca SB 1976). All of these in vitro studieshave suggested that allantoin could be effective in psoriasis, but nopublished clinical data to date with allantoin administration topicallyhave demonstrated efficacy in psoriasis. Results from testing of thistopical formulation at a concentration of allantoin up to 1.5% inclinical psoriasis was consistent with published data on the lack ofhuman clinical efficacy with topically administered allantoin. However,unexpectedly, evaluation of allantoin at a daily administration of thisformulation at a higher concentration (3%), which has been shown todeliver allantoin across the skin barriers, demonstrated completeclearing of psoriatic plaques in addition to prevention of reoccurrenceof plaque formation.

The results of the 3% study demonstrate the ability of allantoin toeffectively close wounds and lesions, and significantly lower than bodysurface area coverage of lesions and wounds in patients with thisindication. Two patients in this study had previously used the 1.5%formulation for an extended period of time, and noted that, while the1.5% formulation was effective, application of the 3% cream was moreeffective in closure of wounds and the healing time was faster. Theseresults are consistent with the findings from the percutaneous skinstudies, in that allantoin can be delivered to the active site moreeffectively at higher cream concentrations resulting in improvedefficacy.

Example 12

Eight patients 6 months to 4 years of age were enrolled an open studywith a 3 month treatment period involving daily administration of 3%allantoin cream to all areas of the body containing blisters, skinerosions and open wounds: 3 patients with EB Simplex; 3 patients withJunctional EB; 2 patients with Recessive Dystrophic EB. All patients hadbetween 25-75% of body surface area affected by the disease.

Measurements: The key measurements were based on a change in diseasecondition from baseline/screening evaluations: (1) the change frombaseline in size of an index lesion/wound measured by area, cm squared;(2) the change from baseline in affected body surface area (BSA)including head, upper limbs, lower limbs, and trunk; physicians globalassessment of improvement from baseline measured on a 6 point scale(Clear; Excellent; Marked; Good; None; Worsening).

Results: The findings of the study indicated that there were clinicallysignificant improvements in BSA and Index lesion scores compared withbaseline. Following 3 months of treatment, there was a 55% reduction inBSA ratings from baseline and in most patients one or more index lesionswere totally healed/cleared. The Physicians Global Assessment ofImprovement indicated that all patients improved from baseline with somepatients showing as much as a 75% improvement. In addition, the creamappeared to prevent the recurrence of newly formed blisters anderosions.

Conclusions: The findings of the study indicated that a 3% concentrationof allantoin in a cream formulation induces a clinically significantchange in the severity of the disease including wound closures and anoverall reduction of body blisters and skin erosions. A number of thesepatients had been exposed previously to a 1.5% concentration ofallantoin cream which was felt to be less efficacious. The currentformulation promotes the penetration of allantoin across the skinbarrier thereby increasing effectiveness in a dose related manner. Basedon the dose-related effects seen with this formulation, it is likelythat higher concentrations may confer even better efficacy.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Accordingly, the present embodiments are to be consideredas illustrative and not restrictive. Therefore the spirit and scope ofthe appended claims should not be limited to the description and thepreferred versions contained within this specification.

1-27. (canceled)
 28. A composition comprising an oil-in-water emulsioncomprising: (a) about 6% allantoin; (b) about 40% to about 90% water;(c) about 8% to about 30% an emollient; (d) about 1% to about 15% anemulsifier; (e) about 0.01% to about 1% a pH modifier; (f) about 1% toabout 10% a viscosity agent; (g) about 1% to about 20% a solubilizingagent selected from the group consisting of propylene glycol, glycerin,and a combination thereof; (h) about 0.01% to about 2% a chelating agentselected from the group consisting of alanine, sodium polyphosphate,sodium methaphosphate, citric acid, phosphoric acid, tartaric acid,dihydroxyethyl glycine, ethylenediamine tetra acetic acid (EDTA) andderivatives and salts thereof, and a combination thereof; (i) about0.001% to about 3% an antioxidant selected from the group consisting ofvitamin B, nordihydroguaiaretic acid, butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid, sodiumerythorbate, ascorbir palmitate, ascorbir stearate, butylhydroxyanisole, and gallic esters; and (j) about 0.01% to about 3.0% apreservative.
 29. The composition of claim 28 comprising: (a) about 6%allantoin; (b) about 40% to about 90% water; (c) about 8% to about 30%emollient selected from the group consisting of lanolin oil, cod liveroil, mineral oil, an alcohol, and any combination thereof; (d) about 1%to about 15% emulsifier selected from the group consisting of sodiumlauryl sulfate, a white wax, and a combination thereof; (e) about 0.01%to about 1% pH modifier selected from the group consisting of citricacid, lactic acid, and a combination thereof; (f) about 1% to about 10%viscosity enhancing agent selected from the group consisting of cetylalcohol, stearyl alcohol, and a combination thereof; (g) about 1% toabout 20% solubilizing agent selected from the group consisting ofpropylene glycol, glycerin, and a combination thereof; (h) about 0.01%to about 2% chelating agent selected from the group consisting ofalanine, sodium polyphosphate, sodium methaphosphate, citric acid,phosphoric acid, tartaric acid, dihydroxyethyl glycine, ethylenediaminetetra acetic acid (EDTA) and derivatives and salts thereof, and acombination thereof; (i) 0.01% to about 1% antioxidant selected from thegroup consisting of vitamin B, nordihydroguaiaretic acid, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbirstearate, butyl hydroxyanisole, and gallic esters; and (j) about 0.01%to about 3.0% preservative selected from the group consisting ofmethylparaben, propylparaben, and a combination thereof.
 30. Thecomposition of claim 29, comprising: (a) about 6% allantoin; (b) about40% to about 90% water; (c) about 1% to about 6% cetyl alcohol; (d)about 1% to about 3% stearyl alcohol; (e) about 1.5% to about 3%beeswax; (f) about 1.5% to about 3% sodium lauryl sulfate in a 30%solution; (g) about 0.05% to about 0.2% citric acid; (h) about 5% toabout 15% lanolin oil; (i) about 2% to about 8% propylene glycol; (j)about 0.05% to about 0.5% tetrasodium EDTA; (k) about 0.05% to about 5%cod liver oil; (l) about 0.05% to about 1% butylated hydroxytoluene; (m)about 0.05% to about 0.5% methylparaben; and (n) about 0.05% to about0.5% propylparaben.
 31. The composition of claim 30, comprising: (a)about 42% to about 68% water; (b) about 2% to about 6% cetyl alcohol;(c) about 1% to about 3% stearyl alcohol; (d) about 1.5% to about 3%beeswax; (e) about 1.5% to about 3% sodium lauryl sulfate in a 30%solution; (f) about 0.06% to about 0.1% citric acid; (g) about 5% toabout 15% lanolin oil; (h) about 2% to about 8% propylene glycol; (i)about 0.05% to about 0.35% tetrasodium EDTA; (j) about 0.05% to about 5%cod liver oil; (k) about 0.05% to about 1% butylated hydroxytoluene; (l)about 0.05% to about 0.5% methylparaben; and (m) about 0.05% to about0.5% propylparaben.
 32. The composition of claim 31, comprising: (a)about 65.11% water; (b) about 3.6% cetyl alcohol; (c) about 1.7% stearylalcohol; (d) about 2.0% beeswax; (e) about 2.0% sodium lauryl sulfate ina 30% solution; (f) about 0.09% citric acid; (g) about 10.6% lanolinoil; (h) about 5.7% propylene glycol; (i) about 0.15% tetrasodium EDTA;(j) about 2% cod liver oil; (k) about 0.5% butylated hydroxytoluene; (l)about 0.3% methylparaben; and (m) about 0.25% propylparaben.
 33. Thecomposition of claim 28 further comprising a fragrance.
 34. A method fortreating epidermolysis bulosa in a patient in need thereof, comprisingcontacting the patient's skin with an effective amount of thecomposition of claim
 28. 35. The method of claim 34, wherein thecomposition is administered to the patient daily.
 36. The method ofclaim 34, wherein the composition results in penetration of theallantoin across the skin membrane of the patient in a dose dependentmanner.
 37. The method of claim 34, wherein the composition results inpenetration of the allantoin across the skin membrane of the patientwithout an increase in systemic blood levels of allantoin in thepatient.